%0 Journal Article %J Blood %D 2021 %T Absent B cells, agammaglobulinemia, and hypertrophic cardiomyopathy in folliculin-interacting protein 1 deficiency. %A Saettini, Francesco %A Poli, Cecilia %A Vengoechea, Jaime %A Bonanomi, Sonia %A Orellana, Julio C %A Fazio, Grazia %A Rodriguez, Fred H %A Noguera, Loreani P %A Booth, Claire %A Jarur-Chamy, Valentina %A Shams, Marissa %A Iascone, Maria %A Vukic, Maja %A Gasperini, Serena %A Quadri, Manuel %A Barroeta Seijas, Amairelys %A Rivers, Elizabeth %A Mauri, Mario %A Badolato, Raffaele %A Cazzaniga, Gianni %A Bugarin, Cristina %A Gaipa, Giuseppe %A Kroes, Wilma G M %A Moratto, Daniele %A van Oostaijen-Ten Dam, Monique M %A Baas, Frank %A van der Maarel, Silvère %A Piazza, Rocco %A Coban-Akdemir, Zeynep H %A James R Lupski %A Bo Yuan %A Chinn, Ivan K %A Daxinger, Lucia %A Biondi, Andrea %K Adult %K Agammaglobulinemia %K Animals %K B-Lymphocytes %K Cardiomyopathy, Hypertrophic %K Carrier Proteins %K Child %K Child, Preschool %K Chromosomes, Human, Pair 5 %K Codon, Nonsense %K Consanguinity %K Crohn Disease %K Developmental Disabilities %K Disease Models, Animal %K Disease Susceptibility %K DNA Copy Number Variations %K Female %K Heart Defects, Congenital %K Humans %K Immunologic Deficiency Syndromes %K Infections %K Loss of Function Mutation %K Lymphopenia %K Male %K Mice %K Neutropenia %K Pedigree %K Uniparental Disomy %K Whole Exome Sequencing %X

Agammaglobulinemia is the most profound primary antibody deficiency that can occur due to an early termination of B-cell development. We here investigated 3 novel patients, including the first known adult, from unrelated families with agammaglobulinemia, recurrent infections, and hypertrophic cardiomyopathy (HCM). Two of them also presented with intermittent or severe chronic neutropenia. We identified homozygous or compound-heterozygous variants in the gene for folliculin interacting protein 1 (FNIP1), leading to loss of the FNIP1 protein. B-cell metabolism, including mitochondrial numbers and activity and phosphatidylinositol 3-kinase/AKT pathway, was impaired. These defects recapitulated the Fnip1-/- animal model. Moreover, we identified either uniparental disomy or copy-number variants (CNVs) in 2 patients, expanding the variant spectrum of this novel inborn error of immunity. The results indicate that FNIP1 deficiency can be caused by complex genetic mechanisms and support the clinical utility of exome sequencing and CNV analysis in patients with broad phenotypes, including agammaglobulinemia and HCM. FNIP1 deficiency is a novel inborn error of immunity characterized by early and severe B-cell development defect, agammaglobulinemia, variable neutropenia, and HCM. Our findings elucidate a functional and relevant role of FNIP1 in B-cell development and metabolism and potentially neutrophil activity.

%B Blood %V 137 %P 493-499 %8 2021 01 28 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/32905580?dopt=Abstract %R 10.1182/blood.2020006441 %0 Journal Article %J Hum Mutat %D 2021 %T Clinical, neuroimaging, and molecular spectrum of TECPR2-associated hereditary sensory and autonomic neuropathy with intellectual disability. %A Neuser, Sonja %A Brechmann, Barbara %A Heimer, Gali %A Brösse, Ines %A Schubert, Susanna %A O'Grady, Lauren %A Zech, Michael %A Srivastava, Siddharth %A Sweetser, David A %A Dincer, Yasemin %A Mall, Volker %A Winkelmann, Juliane %A Behrends, Christian %A Darras, Basil T %A Graham, Robert J %A Jayakar, Parul %A Byrne, Barry %A Bar-Aluma, Bat El %A Haberman, Yael %A Szeinberg, Amir %A Aldhalaan, Hesham M %A Hashem, Mais %A Al Tenaiji, Amal %A Ismayl, Omar %A Al Nuaimi, Asma E %A Maher, Karima %A Ibrahim, Shahnaz %A Khan, Fatima %A Houlden, Henry %A Ramakumaran, Vijayalakshmi S %A Pagnamenta, Alistair T %A Posey, Jennifer E %A James R Lupski %A Tan, Wen-Hann %A ElGhazali, Gehad %A Herman, Isabella %A Muñoz, Tatiana %A Repetto, Gabriela M %A Seitz, Angelika %A Krumbiegel, Mandy %A Poli, Maria Cecilia %A Kini, Usha %A Efthymiou, Stephanie %A Meiler, Jens %A Maroofian, Reza %A Alkuraya, Fowzan S %A Abou Jamra, Rami %A Popp, Bernt %A Ben-Zeev, Bruria %A Ebrahimi-Fakhari, Darius %K Adolescent %K Carrier Proteins %K Child %K Child, Preschool %K Cohort Studies %K Cross-Sectional Studies %K Family %K Female %K Hereditary Sensory and Autonomic Neuropathies %K Humans %K Infant %K Intellectual Disability %K Magnetic Resonance Imaging %K Male %K Models, Molecular %K Mutation, Missense %K Nerve Tissue Proteins %K Neuroimaging %K Pedigree %K Phenotype %K Protein Conformation %X

Bi-allelic TECPR2 variants have been associated with a complex syndrome with features of both a neurodevelopmental and neurodegenerative disorder. Here, we provide a comprehensive clinical description and variant interpretation framework for this genetic locus. Through international collaboration, we identified 17 individuals from 15 families with bi-allelic TECPR2-variants. We systemically reviewed clinical and molecular data from this cohort and 11 cases previously reported. Phenotypes were standardized using Human Phenotype Ontology terms. A cross-sectional analysis revealed global developmental delay/intellectual disability, muscular hypotonia, ataxia, hyporeflexia, respiratory infections, and central/nocturnal hypopnea as core manifestations. A review of brain magnetic resonance imaging scans demonstrated a thin corpus callosum in 52%. We evaluated 17 distinct variants. Missense variants in TECPR2 are predominantly located in the N- and C-terminal regions containing β-propeller repeats. Despite constituting nearly half of disease-associated TECPR2 variants, classifying missense variants as (likely) pathogenic according to ACMG criteria remains challenging. We estimate a pathogenic variant carrier frequency of 1/1221 in the general and 1/155 in the Jewish Ashkenazi populations. Based on clinical, neuroimaging, and genetic data, we provide recommendations for variant reporting, clinical assessment, and surveillance/treatment of individuals with TECPR2-associated disorder. This sets the stage for future prospective natural history studies.

%B Hum Mutat %V 42 %P 762-776 %8 2021 Jun %G eng %N 6 %1 https://www.ncbi.nlm.nih.gov/pubmed/33847017?dopt=Abstract %R 10.1002/humu.24206 %0 Journal Article %J Am J Med Genet A %D 2020 %T Wolff-Parkinson-White syndrome: De novo variants and evidence for mutational burden in genes associated with atrial fibrillation. %A Coban-Akdemir, Zeynep H %A Charng, Wu-Lin %A Azamian, Mahshid %A Paine, Ingrid S %A Punetha, Jaya %A Grochowski, Christopher M %A Gambin, Tomasz %A Valdes, Santiago O %A Cannon, Bryan %A Zapata, Gladys %A Hernandez, Patricia P %A Jhangiani, Shalini %A Harshavardhan Doddapaneni %A Jianhong Hu %A Boricha, Fatima %A Donna M Muzny %A Eric Boerwinkle %A Yang, Yaping %A Richard A Gibbs %A Posey, Jennifer E %A Wehrens, Xander H T %A Belmont, John W %A Kim, Jeffrey J %A Miyake, Christina Y %A James R Lupski %A Lalani, Seema R %K Adolescent %K Adult %K AMP-Activated Protein Kinases %K Ankyrins %K Atrial Fibrillation %K Carrier Proteins %K Child %K Cohort Studies %K Cytoskeletal Proteins %K DNA-Binding Proteins %K Exome Sequencing %K Female %K Genetic Association Studies %K Genetic Predisposition to Disease %K Heart Atria %K Homeodomain Proteins %K Humans %K LIM Domain Proteins %K Male %K Mutation %K Transcription Factors %K Wolff-Parkinson-White Syndrome %K Young Adult %X

BACKGROUND: Wolff-Parkinson-White (WPW) syndrome is a relatively common arrhythmia affecting ~1-3/1,000 individuals. Mutations in PRKAG2 have been described in rare patients in association with cardiomyopathy. However, the genetic basis of WPW in individuals with a structurally normal heart remains poorly understood. Sudden death due to atrial fibrillation (AF) can also occur in these individuals. Several studies have indicated that despite ablation of an accessory pathway, the risk of AF remains high in patients compared to general population.

METHODS: We applied exome sequencing in 305 subjects, including 65 trios, 80 singletons, and 6 multiple affected families. We used de novo analysis, candidate gene approach, and burden testing to explore the genetic contributions to WPW.

RESULTS: A heterozygous deleterious variant in PRKAG2 was identified in one subject, accounting for 0.6% (1/151) of the genetic basis of WPW in this study. Another individual with WPW and left ventricular hypertrophy carried a known pathogenic variant in MYH7. We found rare de novo variants in genes associated with arrhythmia and cardiomyopathy (ANK2, NEBL, PITX2, and PRDM16) in this cohort. There was an increased burden of rare deleterious variants (MAF ≤ 0.005) with CADD score ≥ 25 in genes linked to AF in cases compared to controls (P = .0023).

CONCLUSIONS: Our findings show an increased burden of rare deleterious variants in genes linked to AF in WPW syndrome, suggesting that genetic factors that determine the development of accessory pathways may be linked to an increased susceptibility of atrial muscle to AF in a subset of patients.

%B Am J Med Genet A %V 182 %P 1387-1399 %8 2020 Jun %G eng %N 6 %1 https://www.ncbi.nlm.nih.gov/pubmed/32233023?dopt=Abstract %R 10.1002/ajmg.a.61571 %0 Journal Article %J Genet Med %D 2019 %T Clinical exome sequencing reveals locus heterogeneity and phenotypic variability of cohesinopathies. %A Bo Yuan %A Neira, Juanita %A Pehlivan, Davut %A Santiago-Sim, Teresa %A Song, Xiaofei %A Rosenfeld, Jill %A Posey, Jennifer E %A Patel, Vipulkumar %A Jin, Weihong %A Adam, Margaret P %A Baple, Emma L %A Dean, John %A Fong, Chin-To %A Hickey, Scott E %A Hudgins, Louanne %A Leon, Eyby %A Madan-Khetarpal, Suneeta %A Rawlins, Lettie %A Rustad, Cecilie F %A Stray-Pedersen, Asbjørg %A Tveten, Kristian %A Wenger, Olivia %A Diaz, Jullianne %A Jenkins, Laura %A Martin, Laura %A McGuire, Marianne %A Pietryga, Marguerite %A Ramsdell, Linda %A Slattery, Leah %A Abid, Farida %A Bertuch, Alison A %A Grange, Dorothy %A Immken, Ladonna %A Schaaf, Christian P %A Van Esch, Hilde %A Bi, Weimin %A Cheung, Sau Wai %A Breman, Amy M %A Smith, Janice L %A Shaw, Chad %A Crosby, Andrew H %A Christine M Eng %A Yang, Yaping %A James R Lupski %A Xiao, Rui %A Liu, Pengfei %K Adolescent %K Alleles %K Antigens, Nuclear %K Biological Variation, Population %K Carrier Proteins %K Cell Cycle Proteins %K Child %K Child, Preschool %K Chromosomal Proteins, Non-Histone %K Cohort Studies %K De Lange Syndrome %K Exome %K Female %K Gene Frequency %K Genetic Heterogeneity %K Humans %K INDEL Mutation %K Male %K Mutation %K Nuclear Proteins %K Phenotype %K Polymorphism, Single Nucleotide %K Proto-Oncogene Proteins %K Retrospective Studies %K Whole Exome Sequencing %X

PURPOSE: Defects in the cohesin pathway are associated with cohesinopathies, notably Cornelia de Lange syndrome (CdLS). We aimed to delineate pathogenic variants in known and candidate cohesinopathy genes from a clinical exome perspective.

METHODS: We retrospectively studied patients referred for clinical exome sequencing (CES, N = 10,698). Patients with causative variants in novel or recently described cohesinopathy genes were enrolled for phenotypic characterization.

RESULTS: Pathogenic or likely pathogenic single-nucleotide and insertion/deletion variants (SNVs/indels) were identified in established disease genes including NIPBL (N = 5), SMC1A (N = 14), SMC3 (N = 4), RAD21 (N = 2), and HDAC8 (N = 8). The phenotypes in this genetically defined cohort skew towards the mild end of CdLS spectrum as compared with phenotype-driven cohorts. Candidate or recently reported cohesinopathy genes were supported by de novo SNVs/indels in STAG1 (N = 3), STAG2 (N = 5), PDS5A (N = 1), and WAPL (N = 1), and one inherited SNV in PDS5A. We also identified copy-number deletions affecting STAG1 (two de novo, one of unknown inheritance) and STAG2 (one of unknown inheritance). Patients with STAG1 and STAG2 variants presented with overlapping features yet without characteristic facial features of CdLS.

CONCLUSION: CES effectively identified disease-causing alleles at the mild end of the cohensinopathy spectrum and enabled characterization of candidate disease genes.

%B Genet Med %V 21 %P 663-675 %8 2019 03 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/30158690?dopt=Abstract %R 10.1038/s41436-018-0085-6 %0 Journal Article %J Am J Med Genet A %D 2019 %T Delineating the expanding phenotype associated with SCAPER gene mutation. %A Fasham, James %A Arno, Gavin %A Lin, Siying %A Xu, Mingchu %A Carss, Keren J %A Hull, Sarah %A Lane, Amelia %A Robson, Anthony G %A Wenger, Olivia %A Self, Jay E %A Harlalka, Gaurav V %A Salter, Claire G %A Schema, Lynn %A Moss, Timothy J %A Cheetham, Michael E %A Moore, Anthony T %A Raymond, F Lucy %A Rui Chen %A Baple, Emma L %A Webster, Andrew R %A Crosby, Andrew H %K Adolescent %K Adult %K Carrier Proteins %K Child %K Consanguinity %K DNA Mutational Analysis %K Female %K Genetic Association Studies %K Genetic Predisposition to Disease %K Humans %K Male %K Middle Aged %K Mutation %K Pedigree %K Phenotype %K Young Adult %B Am J Med Genet A %V 179 %P 1665-1671 %8 2019 Aug %G eng %N 8 %1 https://www.ncbi.nlm.nih.gov/pubmed/31192531?dopt=Abstract %R 10.1002/ajmg.a.61202 %0 Journal Article %J J Cell Biol %D 2018 %T SPATA7 maintains a novel photoreceptor-specific zone in the distal connecting cilium. %A Dharmat, Rachayata %A Eblimit, Aiden %A Robichaux, Michael A %A Zhang, Zhixian %A Nguyen, Thanh-Minh T %A Jung, Sung Yun %A He, Feng %A Jain, Antrix %A Yumei Li %A Qin, Jun %A Overbeek, Paul %A Roepman, Ronald %A Mardon, Graeme %A Wensel, Theodore G %A Rui Chen %K Adaptor Proteins, Signal Transducing %K Animals %K Antigens, Neoplasm %K Carrier Proteins %K Cell Cycle Proteins %K Cytoskeletal Proteins %K DNA-Binding Proteins %K Eye Proteins %K Mice %K Mice, Inbred C57BL %K Nuclear Proteins %K Photoreceptor Connecting Cilium %K Protein Transport %X

Photoreceptor-specific ciliopathies often affect a structure that is considered functionally homologous to the ciliary transition zone (TZ) called the connecting cilium (CC). However, it is unclear how mutations in certain ciliary genes disrupt the photoreceptor CC without impacting the primary cilia systemically. By applying stochastic optical reconstruction microscopy technology in different genetic models, we show that the CC can be partitioned into two regions: the proximal CC (PCC), which is homologous to the TZ of primary cilia, and the distal CC (DCC), a photoreceptor-specific extension of the ciliary TZ. This specialized distal zone of the CC in photoreceptors is maintained by SPATA7, which interacts with other photoreceptor-specific ciliary proteins such as RPGR and RPGRIP1. The absence of results in the mislocalization of DCC proteins without affecting the PCC protein complexes. This collapse results in destabilization of the axonemal microtubules, which consequently results in photoreceptor degeneration. These data provide a novel mechanism to explain how genetic disruption of ubiquitously present ciliary proteins exerts tissue-specific ciliopathy phenotypes.

%B J Cell Biol %V 217 %P 2851-2865 %8 2018 Aug 06 %G eng %N 8 %1 https://www.ncbi.nlm.nih.gov/pubmed/29899041?dopt=Abstract %R 10.1083/jcb.201712117 %0 Journal Article %J Hum Genet %D 2017 %T Haploinsufficiency of the E3 ubiquitin-protein ligase gene TRIP12 causes intellectual disability with or without autism spectrum disorders, speech delay, and dysmorphic features. %A Zhang, Jing %A Gambin, Tomasz %A Bo Yuan %A Szafranski, Przemyslaw %A Rosenfeld, Jill A %A Balwi, Mohammed Al %A Alswaid, Abdulrahman %A Al-Gazali, Lihadh %A Shamsi, Aisha M Al %A Komara, Makanko %A Ali, Bassam R %A Roeder, Elizabeth %A McAuley, Laura %A Roy, Daniel S %A Manchester, David K %A Magoulas, Pilar %A King, Lauren E %A Hannig, Vickie %A Bonneau, Dominique %A Denommé-Pichon, Anne-Sophie %A Charif, Majida %A Besnard, Thomas %A Bézieau, Stéphane %A Cogné, Benjamin %A Andrieux, Joris %A Zhu, Wenmiao %A He, Weimin %A Vetrini, Francesco %A Ward, Patricia A %A Cheung, Sau Wai %A Bi, Weimin %A Eng, Christine M %A Lupski, James R %A Yang, Yaping %A Patel, Ankita %A Lalani, Seema R %A Xia, Fan %A Stankiewicz, Paweł %K Adolescent %K Autism Spectrum Disorder %K Carrier Proteins %K Child %K Child, Preschool %K Cohort Studies %K DNA Copy Number Variations %K Facies %K Female %K Haploinsufficiency %K Humans %K Infant %K Intellectual Disability %K Language Development Disorders %K Male %K Ubiquitin-Protein Ligases %X

Impairment of ubiquitin-proteasome system activity involving ubiquitin ligase genes UBE3A, UBE3B, and HUWE1 and deubiquitinating enzyme genes USP7 and USP9X has been reported in patients with neurodevelopmental delays. To date, only a handful of single-nucleotide variants (SNVs) and copy-number variants (CNVs) involving TRIP12, encoding a member of the HECT domain E3 ubiquitin ligases family on chromosome 2q36.3 have been reported. Using chromosomal microarray analysis and whole-exome sequencing (WES), we have identified, respectively, five deletion CNVs and four inactivating SNVs (two frameshifts, one missense, and one splicing) in TRIP12. Seven of these variants were found to be de novo; parental studies could not be completed in two families. Quantitative PCR analyses of the splicing mutation showed a dramatically decreased level of TRIP12 mRNA in the proband compared to the family controls, indicating a loss-of-function mechanism. The shared clinical features include intellectual disability with or without autistic spectrum disorders, speech delay, and facial dysmorphism. Our findings demonstrate that E3 ubiquitin ligase TRIP12 plays an important role in nervous system development and function. The nine presented pathogenic variants further document that TRIP12 haploinsufficiency causes a childhood-onset neurodevelopmental disorder. Finally, our data enable expansion of the phenotypic spectrum of ubiquitin-proteasome dependent disorders.

%B Hum Genet %V 136 %P 377-386 %8 2017 Apr %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/28251352?dopt=Abstract %R 10.1007/s00439-017-1763-1 %0 Journal Article %J J Hum Genet %D 2017 %T Kaufman oculo-cerebro-facial syndrome in a child with small and absent terminal phalanges and absent nails. %A Kariminejad, Ariana %A Ajeawung, Norbert Fonya %A Bozorgmehr, Bita %A Dionne-Laporte, Alexandre %A Molidperee, Sirinart %A Najafi, Kimia %A Richard A Gibbs %A Lee, Brendan H %A Hennekam, Raoul C %A Campeau, Philippe M %K Abnormalities, Multiple %K Adult %K Carrier Proteins %K Child %K Child, Preschool %K Diagnosis, Differential %K Eczema %K Eye Abnormalities %K Face %K Facies %K Female %K Growth Disorders %K GTPase-Activating Proteins %K Hand Deformities, Congenital %K Humans %K Intellectual Disability %K Karyotype %K Limb Deformities, Congenital %K Male %K Membrane Proteins %K Microcephaly %K Micrognathism %K Mutation %K Neck %K Nerve Tissue Proteins %K Pathology, Molecular %K Sequence Analysis, DNA %K Ubiquitin-Protein Ligases %X

Kaufman oculo-cerebro-facial syndrome (KOS) is caused by recessive UBE3B mutations and presents with microcephaly, ocular abnormalities, distinctive facial morphology, low cholesterol levels and intellectual disability. We describe a child with microcephaly, brachycephaly, hearing loss, ptosis, blepharophimosis, hypertelorism, cleft palate, multiple renal cysts, absent nails, small or absent terminal phalanges, absent speech and intellectual disability. Syndromes that were initially considered include DOORS syndrome, Coffin-Siris syndrome and Dubowitz syndrome. Clinical investigations coupled with karyotype analysis, array-comparative genomic hybridization, exome and Sanger sequencing were performed to characterize the condition in this child. Sanger sequencing was negative for the DOORS syndrome gene TBC1D24 but exome sequencing identified a homozygous deletion in UBE3B (NM_183415:c.3139_3141del, p.1047_1047del) located within the terminal portion of the HECT domain. This finding coupled with the presence of characteristic features such as brachycephaly, ptosis, blepharophimosis, hypertelorism, short palpebral fissures, cleft palate and developmental delay allowed us to make a diagnosis of KOS. In conclusion, our findings highlight the importance of considering KOS as a differential diagnosis for patients under evaluation for DOORS syndrome and expand the phenotype of KOS to include small or absent terminal phalanges, nails, and the presence of hallux varus and multicystic dysplastic kidneys.

%B J Hum Genet %V 62 %P 465-471 %8 2017 Apr %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/28003643?dopt=Abstract %R 10.1038/jhg.2016.151 %0 Journal Article %J Brain %D 2017 %T PRUNE is crucial for normal brain development and mutated in microcephaly with neurodevelopmental impairment. %A Zollo, Massimo %A Ahmed, Mustafa %A Ferrucci, Veronica %A Salpietro, Vincenzo %A Asadzadeh, Fatemeh %A Carotenuto, Marianeve %A Maroofian, Reza %A Al-Amri, Ahmed %A Singh, Royana %A Scognamiglio, Iolanda %A Mojarrad, Majid %A Musella, Luca %A Duilio, Angela %A Di Somma, Angela %A Karaca, Ender %A Rajab, Anna %A Al-Khayat, Aisha %A Mohan Mohapatra, Tribhuvan %A Eslahi, Atieh %A Ashrafzadeh, Farah %A Rawlins, Lettie E %A Prasad, Rajniti %A Gupta, Rashmi %A Kumari, Preeti %A Srivastava, Mona %A Cozzolino, Flora %A Kumar Rai, Sunil %A Monti, Maria %A Harlalka, Gaurav V %A Simpson, Michael A %A Rich, Philip %A Al-Salmi, Fatema %A Patton, Michael A %A Chioza, Barry A %A Efthymiou, Stephanie %A Granata, Francesca %A Di Rosa, Gabriella %A Wiethoff, Sarah %A Borgione, Eugenia %A Scuderi, Carmela %A Mankad, Kshitij %A Hanna, Michael G %A Pucci, Piero %A Houlden, Henry %A Lupski, James R %A Crosby, Andrew H %A Baple, Emma L %K Adolescent %K Brain %K Carrier Proteins %K Cell Differentiation %K Cell Movement %K Cerebral Cortex %K Child %K Child, Preschool %K Cytoskeleton %K Developmental Disabilities %K Female %K Genes, Recessive %K Heredodegenerative Disorders, Nervous System %K Humans %K Infant %K Male %K Microcephaly %K Microtubules %K Mutation %K Pedigree %K Phosphoric Monoester Hydrolases %K Young Adult %X

PRUNE is a member of the DHH (Asp-His-His) phosphoesterase protein superfamily of molecules important for cell motility, and implicated in cancer progression. Here we investigated multiple families from Oman, India, Iran and Italy with individuals affected by a new autosomal recessive neurodevelopmental and degenerative disorder in which the cardinal features include primary microcephaly and profound global developmental delay. Our genetic studies identified biallelic mutations of PRUNE1 as responsible. Our functional assays of disease-associated variant alleles revealed impaired microtubule polymerization, as well as cell migration and proliferation properties, of mutant PRUNE. Additionally, our studies also highlight a potential new role for PRUNE during microtubule polymerization, which is essential for the cytoskeletal rearrangements that occur during cellular division and proliferation. Together these studies define PRUNE as a molecule fundamental for normal human cortical development and define cellular and clinical consequences associated with PRUNE mutation.

%B Brain %V 140 %P 940-952 %8 2017 Apr 01 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/28334956?dopt=Abstract %R 10.1093/brain/awx014 %0 Journal Article %J Am J Hum Genet %D 2016 %T Biallelic Mutations in UNC80 Cause Persistent Hypotonia, Encephalopathy, Growth Retardation, and Severe Intellectual Disability. %A Stray-Pedersen, Asbjørg %A Cobben, Jan-Maarten %A Prescott, Trine E %A Lee, Sora %A Cang, Chunlei %A Aranda, Kimberly %A Ahmed, Sohnee %A Alders, Marielle %A Gerstner, Thorsten %A Aslaksen, Kathinka %A Tétreault, Martine %A Qin, Wen %A Hartley, Taila %A Jhangiani, Shalini N %A Donna M Muzny %A Tarailo-Graovac, Maja %A van Karnebeek, Clara D M %A Lupski, James R %A Ren, Dejian %A Yoon, Grace %K Adolescent %K Alleles %K Brain Diseases %K Carrier Proteins %K Child %K Child, Preschool %K Female %K Growth Disorders %K Humans %K Intellectual Disability %K Membrane Proteins %K Muscle Hypotonia %K Mutation %K Severity of Illness Index %X

Ion channel proteins are required for both the establishment of resting membrane potentials and the generation of action potentials. Hundreds of mutations in genes encoding voltage-gated ion channels responsible for action potential generation have been found to cause severe neurological diseases. In contrast, the roles of voltage-independent "leak" channels, important for the establishment and maintenance of resting membrane potentials upon which action potentials are generated, are not well established in human disease. UNC80 is a large component of the NALCN sodium-leak channel complex that regulates the basal excitability of the nervous system. Loss-of-function mutations of NALCN cause infantile hypotonia with psychomotor retardation and characteristic facies (IHPRF). We report four individuals from three unrelated families who have homozygous missense or compound heterozygous truncating mutations in UNC80 and persistent hypotonia, encephalopathy, growth failure, and severe intellectual disability. Compared to control cells, HEK293T cells transfected with an expression plasmid containing the c.5098C>T (p.Pro1700Ser) UNC80 mutation found in one individual showed markedly decreased NALCN channel currents. Our findings demonstrate the fundamental significance of UNC80 and basal ionic conductance to human health.

%B Am J Hum Genet %V 98 %P 202-9 %8 2016 Jan 07 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/26708751?dopt=Abstract %R 10.1016/j.ajhg.2015.11.004 %0 Journal Article %J Hum Mutat %D 2016 %T Identification of Intellectual Disability Genes in Female Patients with a Skewed X-Inactivation Pattern. %A Fieremans, Nathalie %A Van Esch, Hilde %A Holvoet, Maureen %A Van Goethem, Gert %A Devriendt, Koenraad %A Rosello, Monica %A Mayo, Sonia %A Martinez, Francisco %A Jhangiani, Shalini %A Donna M Muzny %A Richard A Gibbs %A Lupski, James R %A Vermeesch, Joris R %A Marynen, Peter %A Froyen, Guy %K Carrier Proteins %K Cell Cycle Proteins %K Chromosomal Proteins, Non-Histone %K DEAD-box RNA Helicases %K Exome %K Female %K Genetic Variation %K Humans %K Intellectual Disability %K Membrane Proteins %K Methyl-CpG-Binding Protein 2 %K Nuclear Proteins %K Sequence Analysis, DNA %K X Chromosome Inactivation %X

Intellectual disability (ID) is a heterogeneous disorder with an unknown molecular etiology in many cases. Previously, X-linked ID (XLID) studies focused on males because of the hemizygous state of their X chromosome. Carrier females are generally unaffected because of the presence of a second normal allele, or inactivation of the mutant X chromosome in most of their cells (skewing). However, in female ID patients, we hypothesized that the presence of skewing of X-inactivation would be an indicator for an X chromosomal ID cause. We analyzed the X-inactivation patterns of 288 females with ID, and found that 22 (7.6%) had extreme skewing (>90%), which is significantly higher than observed in the general population (3.6%; P = 0.029). Whole-exome sequencing of 19 females with extreme skewing revealed causal variants in six females in the XLID genes DDX3X, NHS, WDR45, MECP2, and SMC1A. Interestingly, variants in genes escaping X-inactivation presumably cause both XLID and skewing of X-inactivation in three of these patients. Moreover, variants likely accounting for skewing only were detected in MED12, HDAC8, and TAF9B. All tested candidate causative variants were de novo events. Hence, extreme skewing is a good indicator for the presence of X-linked variants in female patients.

%B Hum Mutat %V 37 %P 804-11 %8 2016 Aug %G eng %N 8 %1 https://www.ncbi.nlm.nih.gov/pubmed/27159028?dopt=Abstract %R 10.1002/humu.23012 %0 Journal Article %J Hum Genet %D 2015 %T Mutations in human IFT140 cause non-syndromic retinal degeneration. %A Xu, Mingchu %A Yang, Lizhu %A Wang, Feng %A Li, Huajin %A Wang, Xia %A Wang, Weichen %A Ge, Zhongqi %A Wang, Keqing %A Zhao, Li %A Li, Hui %A Yumei Li %A Sui, Ruifang %A Rui Chen %K Adult %K Amino Acid Sequence %K Carrier Proteins %K Child %K Female %K Genetic Association Studies %K Humans %K Leber Congenital Amaurosis %K Male %K Middle Aged %K Mutation, Missense %K Pedigree %K Retinitis Pigmentosa %X

Leber congenital amaurosis (LCA) and retinitis pigmentosa (RP) are two genetically heterogeneous retinal degenerative disorders. Despite the identification of a number of genes involved in LCA and RP, the genetic etiology remains unknown in many patients. In this study, we aimed to identify novel disease-causing genes of LCA and RP. Retinal capture sequencing was initially performed to screen mutations in known disease-causing genes in different cohorts of LCA and RP patients. For patients with negative results, we performed whole exome sequencing and applied a series of variant filtering strategies. Sanger sequencing was done to validate candidate causative IFT140 variants. Exome sequencing data analysis led to the identification of IFT140 variants in multiple unrelated non-syndromic LCA and RP cases. All the variants are extremely rare and predicted to be damaging. All the variants passed Sanger validation and segregation tests provided that the family members' DNA was available. The results expand the phenotype spectrum of IFT140 mutations to non-syndromic retinal degeneration, thus extending our understanding of intraflagellar transport and primary cilia biology in the retina. This work also improves the molecular diagnosis of retinal degenerative disease.

%B Hum Genet %V 134 %P 1069-78 %8 2015 Oct %G eng %N 10 %1 https://www.ncbi.nlm.nih.gov/pubmed/26216056?dopt=Abstract %R 10.1007/s00439-015-1586-x %0 Journal Article %J Pharmacogenomics J %D 2015 %T Transethnic meta-analysis suggests genetic variation in the HEME pathway influences potassium response in patients treated with hydrochlorothiazide. %A Del-Aguila, J L %A Cooper-Dehoff, R M %A Chapman, A B %A Gums, J G %A Beitelshees, A L %A Bailey, K %A Turner, S T %A Johnson, J A %A Eric Boerwinkle %K Antihypertensive Agents %K Bayes Theorem %K Black or African American %K Carrier Proteins %K Cation Transport Proteins %K Chromosomes, Human, Pair 12 %K Chromosomes, Human, Pair 8 %K Female %K Genome-Wide Association Study %K Heme %K Heme-Binding Proteins %K Hemeproteins %K Humans %K Hydrochlorothiazide %K Hypertension %K Hypokalemia %K Male %K Middle Aged %K Mitochondrial Proteins %K Polymorphism, Single Nucleotide %K Potassium %K White People %X

Hypokalemia is a recognized adverse effect of thiazide diuretic treatment. This phenomenon, which may impair insulin secretion, has been suggested to be a reason for the adverse effects on glucose metabolism associated with thiazide diuretic treatment of hypertension. However, the mechanisms underlying thiazide diuretic-induced hypokalemia are not well understood. In an effort to identify genes or genomic regions associated with potassium response to hydrochlorothiazide, without a priori knowledge of biologic effects, we performed a genome-wide association study and a multiethnic meta-analysis in 718 European- and African-American hypertensive participants from two different pharmacogenetic studies. Single-nucleotide polymorphisms rs10845697 (Bayes factor=5.560) on chromosome 12, near to the HEME binding protein 1 gene, and rs11135740 (Bayes factor=5.258) on chromosome 8, near to the Mitoferrin-1 gene, reached genome-wide association study significance (Bayes factor >5). These results, if replicated, suggest a novel mechanism involving effects of genes in the HEME pathway influencing hydrochlorothiazide-induced renal potassium loss.

%B Pharmacogenomics J %V 15 %P 153-7 %8 2015 Apr %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/25201287?dopt=Abstract %R 10.1038/tpj.2014.46 %0 Journal Article %J Ophthalmic Genet %D 2015 %T Whole Exome Sequencing Identifies an Adult-Onset Case of Methylmalonic Aciduria and Homocystinuria Type C (cblC) with Non-Syndromic Bull's Eye Maculopathy. %A Collison, Frederick T %A Xie, Yajing Angela %A Gambin, Tomasz %A Jhangiani, Shalini %A Donna M Muzny %A Richard A Gibbs %A Lupski, James R %A Fishman, Gerald A %A Allikmets, Rando %K Adult %K Carrier Proteins %K Electroretinography %K Exome %K Female %K Genetic Testing %K Heterozygote %K Homocystinuria %K Humans %K Macular Degeneration %K Mutation %K Oxidoreductases %K Pedigree %K Scotoma %K Sequence Analysis, DNA %K Tomography, Optical Coherence %K Visual Acuity %K Visual Fields %K Vitamin B 12 %K Vitamin B 12 Deficiency %K Vitamin B Complex %X

BACKGROUND: Methylmalonic aciduria and homocystinuria type C (cblC), a disorder of vitamin B12 (cobalamin) metabolism caused by mutations in the MMACHC gene, presents with many systemic symptoms, including neurological, cognitive, psychiatric, and thromboembolic events. Retinal phenotypes, including maculopathy, pigmentary retinopathy, and optic atrophy are common in early onset form of the disease but are rare in adult onset forms.

MATERIALS AND METHODS: An adult Hispanic female presented with decreased central vision, bilateral pericentral ring scotomas and bull's eye-appearing macular lesions at 28 years of age. Her medical history was otherwise unremarkable except for iron deficiency anemia and both urinary tract and kidney infections. Screening of the ABCA4 gene, mutations in which frequently cause bull's eye maculopathy, was negative. Subsequently, analysis with whole exome sequencing was performed.

RESULTS: Whole exome sequencing discovered compound heterozygous mutations in MMACHC, c.G482A:p.Arg161Gln and c.270_271insA:p.Arg91Lysfs*14, which segregated with the disease in the family. The genetic diagnosis was confirmed by biochemical laboratory testing, showing highly elevated urine methylmalonic acid/creatinine and homocysteine levels, and suggesting disease management with hydroxycobalamin injections and carnitine supplementation.

CONCLUSIONS: In summary, a unique case of an adult patient with bull's eye macular lesions and no clinically relevant systemic symptoms was diagnosed with cblC by genetic screening and follow-up biochemical laboratory tests.

%B Ophthalmic Genet %V 36 %P 270-5 %8 2015 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/25687216?dopt=Abstract %R 10.3109/13816810.2015.1010736 %0 Journal Article %J Lancet Neurol %D 2014 %T The genetic basis of DOORS syndrome: an exome-sequencing study. %A Campeau, Philippe M %A Kasperaviciute, Dalia %A Lu, James T %A Burrage, Lindsay C %A Kim, Choel %A Hori, Mutsuki %A Powell, Berkley R %A Stewart, Fiona %A Félix, Têmis Maria %A van den Ende, Jenneke %A Wisniewska, Marzena %A Kayserili, Hulya %A Rump, Patrick %A Nampoothiri, Sheela %A Aftimos, Salim %A Mey, Antje %A Nair, Lal D V %A Begleiter, Michael L %A De Bie, Isabelle %A Meenakshi, Girish %A Murray, Mitzi L %A Repetto, Gabriela M %A Golabi, Mahin %A Blair, Edward %A Male, Alison %A Giuliano, Fabienne %A Kariminejad, Ariana %A Newman, William G %A Bhaskar, Sanjeev S %A Dickerson, Jonathan E %A Kerr, Bronwyn %A Banka, Siddharth %A Giltay, Jacques C %A Wieczorek, Dagmar %A Tostevin, Anna %A Wiszniewska, Joanna %A Cheung, Sau Wai %A Hennekam, Raoul C %A Richard A Gibbs %A Lee, Brendan H %A Sisodiya, Sanjay M %K Adolescent %K Carrier Proteins %K Child %K Child, Preschool %K Craniofacial Abnormalities %K Exome %K Female %K GTPase-Activating Proteins %K Hand Deformities, Congenital %K Hearing Loss, Sensorineural %K Humans %K Infant %K Intellectual Disability %K Internationality %K Male %K Membrane Proteins %K Nails, Malformed %K Nerve Tissue Proteins %K Phenotype %K Sequence Analysis, DNA %K Young Adult %X

BACKGROUND: Deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures (DOORS) syndrome is a rare autosomal recessive disorder of unknown cause. We aimed to identify the genetic basis of this syndrome by sequencing most coding exons in affected individuals.

METHODS: Through a search of available case studies and communication with collaborators, we identified families that included at least one individual with at least three of the five main features of the DOORS syndrome: deafness, onychodystrophy, osteodystrophy, intellectual disability, and seizures. Participants were recruited from 26 centres in 17 countries. Families described in this study were enrolled between Dec 1, 2010, and March 1, 2013. Collaborating physicians enrolling participants obtained clinical information and DNA samples from the affected child and both parents if possible. We did whole-exome sequencing in affected individuals as they were enrolled, until we identified a candidate gene, and Sanger sequencing to confirm mutations. We did expression studies in human fibroblasts from one individual by real-time PCR and western blot analysis, and in mouse tissues by immunohistochemistry and real-time PCR.

FINDINGS: 26 families were included in the study. We did exome sequencing in the first 17 enrolled families; we screened for TBC1D24 by Sanger sequencing in subsequent families. We identified TBC1D24 mutations in 11 individuals from nine families (by exome sequencing in seven families, and Sanger sequencing in two families). 18 families had individuals with all five main features of DOORS syndrome, and TBC1D24 mutations were identified in half of these families. The seizure types in individuals with TBC1D24 mutations included generalised tonic-clonic, complex partial, focal clonic, and infantile spasms. Of the 18 individuals with DOORS syndrome from 17 families without TBC1D24 mutations, eight did not have seizures and three did not have deafness. In expression studies, some mutations abrogated TBC1D24 mRNA stability. We also detected Tbc1d24 expression in mouse phalangeal chondrocytes and calvaria, which suggests a role of TBC1D24 in skeletogenesis.

INTERPRETATION: Our findings suggest that mutations in TBC1D24 seem to be an important cause of DOORS syndrome and can cause diverse phenotypes. Thus, individuals with DOORS syndrome without deafness and seizures but with the other features should still be screened for TBC1D24 mutations. More information is needed to understand the cellular roles of TBC1D24 and identify the genes responsible for DOORS phenotypes in individuals who do not have a mutation in TBC1D24.

FUNDING: US National Institutes of Health, the CIHR (Canada), the NIHR (UK), the Wellcome Trust, the Henry Smith Charity, and Action Medical Research.

%B Lancet Neurol %V 13 %P 44-58 %8 2014 Jan %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/24291220?dopt=Abstract %R 10.1016/S1474-4422(13)70265-5 %0 Journal Article %J PLoS One %D 2014 %T Gene-wide analysis detects two new susceptibility genes for Alzheimer's disease. %A Escott-Price, Valentina %A Bellenguez, Céline %A Wang, Li-San %A Choi, Seung-Hoan %A Harold, Denise %A Jones, Lesley %A Holmans, Peter %A Gerrish, Amy %A Vedernikov, Alexey %A Richards, Alexander %A DeStefano, Anita L %A Lambert, Jean-Charles %A Ibrahim-Verbaas, Carla A %A Naj, Adam C %A Sims, Rebecca %A Jun, Gyungah %A Bis, Joshua C %A Beecham, Gary W %A Grenier-Boley, Benjamin %A Russo, Giancarlo %A Thornton-Wells, Tricia A %A Denning, Nicola %A Smith, Albert V %A Chouraki, Vincent %A Thomas, Charlene %A Ikram, M Arfan %A Zelenika, Diana %A Vardarajan, Badri N %A Kamatani, Yoichiro %A Lin, Chiao-Feng %A Schmidt, Helena %A Kunkle, Brian %A Dunstan, Melanie L %A Vronskaya, Maria %A Johnson, Andrew D %A Ruiz, Agustin %A Bihoreau, Marie-Therese %A Reitz, Christiane %A Pasquier, Florence %A Hollingworth, Paul %A Hanon, Olivier %A Fitzpatrick, Annette L %A Buxbaum, Joseph D %A Campion, Dominique %A Crane, Paul K %A Baldwin, Clinton %A Becker, Tim %A Gudnason, Vilmundur %A Cruchaga, Carlos %A Craig, David %A Amin, Najaf %A Berr, Claudine %A Lopez, Oscar L %A De Jager, Philip L %A Deramecourt, Vincent %A Johnston, Janet A %A Evans, Denis %A Lovestone, Simon %A Letenneur, Luc %A Hernández, Isabel %A Rubinsztein, David C %A Eiriksdottir, Gudny %A Sleegers, Kristel %A Goate, Alison M %A Fiévet, Nathalie %A Huentelman, Matthew J %A Gill, Michael %A Brown, Kristelle %A Kamboh, M Ilyas %A Keller, Lina %A Barberger-Gateau, Pascale %A McGuinness, Bernadette %A Larson, Eric B %A Myers, Amanda J %A Dufouil, Carole %A Todd, Stephen %A Wallon, David %A Love, Seth %A Rogaeva, Ekaterina %A Gallacher, John %A George-Hyslop, Peter St %A Clarimon, Jordi %A Lleo, Alberto %A Bayer, Anthony %A Tsuang, Debby W %A Yu, Lei %A Tsolaki, Magda %A Bossù, Paola %A Spalletta, Gianfranco %A Proitsi, Petra %A Collinge, John %A Sorbi, Sandro %A Garcia, Florentino Sanchez %A Fox, Nick C %A Hardy, John %A Naranjo, Maria Candida Deniz %A Bosco, Paolo %A Clarke, Robert %A Brayne, Carol %A Galimberti, Daniela %A Scarpini, Elio %A Bonuccelli, Ubaldo %A Mancuso, Michelangelo %A Siciliano, Gabriele %A Moebus, Susanne %A Mecocci, Patrizia %A Zompo, Maria Del %A Maier, Wolfgang %A Hampel, Harald %A Pilotto, Alberto %A Frank-García, Ana %A Panza, Francesco %A Solfrizzi, Vincenzo %A Caffarra, Paolo %A Nacmias, Benedetta %A Perry, William %A Mayhaus, Manuel %A Lannfelt, Lars %A Hakonarson, Hakon %A Pichler, Sabrina %A Carrasquillo, Minerva M %A Ingelsson, Martin %A Beekly, Duane %A Alvarez, Victoria %A Zou, Fanggeng %A Valladares, Otto %A Younkin, Steven G %A Coto, Eliecer %A Hamilton-Nelson, Kara L %A Gu, Wei %A Razquin, Cristina %A Pastor, Pau %A Mateo, Ignacio %A Owen, Michael J %A Faber, Kelley M %A Jonsson, Palmi V %A Combarros, Onofre %A O'Donovan, Michael C %A Cantwell, Laura B %A Soininen, Hilkka %A Blacker, Deborah %A Mead, Simon %A Mosley, Thomas H %A Bennett, David A %A Harris, Tamara B %A Fratiglioni, Laura %A Holmes, Clive %A de Bruijn, Renee F A G %A Passmore, Peter %A Montine, Thomas J %A Bettens, Karolien %A Rotter, Jerome I %A Brice, Alexis %A Morgan, Kevin %A Foroud, Tatiana M %A Kukull, Walter A %A Hannequin, Didier %A Powell, John F %A Nalls, Michael A %A Ritchie, Karen %A Lunetta, Kathryn L %A Kauwe, John S K %A Eric Boerwinkle %A Riemenschneider, Matthias %A Boada, Mercè %A Hiltunen, Mikko %A Martin, Eden R %A Schmidt, Reinhold %A Rujescu, Dan %A Dartigues, Jean-François %A Mayeux, Richard %A Tzourio, Christophe %A Hofman, Albert %A Nöthen, Markus M %A Graff, Caroline %A Psaty, Bruce M %A Haines, Jonathan L %A Lathrop, Mark %A Pericak-Vance, Margaret A %A Launer, Lenore J %A Van Broeckhoven, Christine %A Farrer, Lindsay A %A van Duijn, Cornelia M %A Ramirez, Alfredo %A Seshadri, Sudha %A Schellenberg, Gerard D %A Amouyel, Philippe %A Williams, Julie %K Alzheimer Disease %K Carrier Proteins %K Case-Control Studies %K Genome-Wide Association Study %K Heat-Shock Proteins %K Humans %K Polymorphism, Single Nucleotide %K Receptors, Antigen, B-Cell %X

BACKGROUND: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls.

PRINCIPAL FINDINGS: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10-6) and 14 (IGHV1-67 p = 7.9×10-8) which indexed novel susceptibility loci.

SIGNIFICANCE: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.

%B PLoS One %V 9 %P e94661 %8 2014 %G eng %N 6 %1 https://www.ncbi.nlm.nih.gov/pubmed/24922517?dopt=Abstract %R 10.1371/journal.pone.0094661 %0 Journal Article %J Am J Med Genet B Neuropsychiatr Genet %D 2009 %T Common and rare variants of DAOA in bipolar disorder. %A Maheshwari, Manjula %A Shi, Jiajun %A Badner, Judith A %A Skol, Andrew %A Willour, Virginia L %A Muzny, Donna M %A Wheeler, David A %A Gerald, Fowler R %A Detera-Wadleigh, Sevilla %A McMahon, Francis J %A Potash, James B %A Gershon, Elliot S %A Liu, Chunyu %A Gibbs, Richard A %K Bipolar Disorder %K Carrier Proteins %K Cloning, Molecular %K Exons %K Female %K Genetic Predisposition to Disease %K Humans %K Intracellular Signaling Peptides and Proteins %K Male %K Polymorphism, Single Nucleotide %K Sequence Analysis, DNA %X

The D-amino acid oxidase activator (DAOA, previously known as G72) gene, mapped on 13q33, has been reported to be genetically associated with bipolar disorder (BP) in several populations. The consistency of associated variants is unclear and rare variants in exons of the DAOA gene have not been investigated in psychiatric diseases. We employed a conditional linkage method-STatistical Explanation for Positional Cloning (STEPC) to evaluate whether any associated single nucleotide polymorphisms (SNPs) account for the evidence of linkage in a pedigree series that previously has been linked to marker D13S779 at 13q33. We also performed an association study in a sample of 376 Caucasian BP parent-proband trios by genotyping 38 common SNPs in the gene region. Besides, we resequenced coding regions and flanking intronic sequences of DAOA in 555 Caucasian unrelated BP patients and 564 mentally healthy controls, to identify putative functional rare variants that may contribute to disease. One SNP rs1935058 could "explain" the linkage signal in the family sample set (P = 0.055) using STEPC analysis. No significant allelic association was detected in an association study by genotyping 38 common SNPs in 376 Caucasian BP trios. Resequencing identified 53 SNPs, of which 46 were novel SNPs. There was no significant excess of rare variants in cases relative to controls. Our results suggest that DAOA does not have a major effect on BP susceptibility. However, DAOA may contribute to bipolar susceptibility in some specific families as evidenced by the STEPC analysis.

%B Am J Med Genet B Neuropsychiatr Genet %V 150B %P 960-6 %8 2009 Oct 05 %G eng %N 7 %1 https://www.ncbi.nlm.nih.gov/pubmed/19194963?dopt=Abstract %R 10.1002/ajmg.b.30925 %0 Journal Article %J Mol Plant Microbe Interact %D 2009 %T Complete genome sequence of citrus huanglongbing bacterium, 'Candidatus Liberibacter asiaticus' obtained through metagenomics. %A Duan, Yongping %A Zhou, Lijuan %A Hall, David G %A Li, Wenbin %A Harshavardhan Doddapaneni %A Lin, Hong %A Liu, Li %A Vahling, Cheryl M %A Gabriel, Dean W %A Williams, Kelly P %A Dickerman, Allan %A Sun, Yijun %A Gottwald, Tim %K Animals %K Bacterial Proteins %K Carrier Proteins %K Citrus %K Genome, Bacterial %K Genomics %K Hemiptera %K Molecular Sequence Data %K Phylogeny %K Rhizobiaceae %K Sequence Analysis, DNA %K Symbiosis %X

Citrus huanglongbing is the most destructive disease of citrus worldwide. It is spread by citrus psyllids and is associated with a low-titer, phloem-limited infection by any of three uncultured species of alpha-Proteobacteria, 'Candidatus Liberibacter asiaticus', 'Ca. L. americanus', and 'Ca. L. africanus'. A complete circular 'Ca. L. asiaticus' genome has been obtained by metagenomics, using the DNA extracted from a single 'Ca. L. asiaticus'-infected psyllid. The 1.23-Mb genome has an average 36.5% GC content. Annotation revealed a high percentage of genes involved in both cell motility (4.5%) and active transport in general (8.0%), which may contribute to its virulence. 'Ca. L. asiaticus' appears to have a limited ability for aerobic respiration and is likely auxotrophic for at least five amino acids. Consistent with its intracellular nature, 'Ca. L. asiaticus' lacks type III and type IV secretion systems as well as typical free-living or plant-colonizing extracellular degradative enzymes. 'Ca. L. asiaticus' appears to have all type I secretion system genes needed for both multidrug efflux and toxin effector secretion. Multi-protein phylogenetic analysis confirmed 'Ca. L. asiaticus' as an early-branching and highly divergent member of the family Rhizobiaceae. This is the first genome sequence of an uncultured alpha-proteobacteria that is both an intracellular plant pathogen and insect symbiont.

%B Mol Plant Microbe Interact %V 22 %P 1011-20 %8 2009 Aug %G eng %N 8 %1 https://www.ncbi.nlm.nih.gov/pubmed/19589076?dopt=Abstract %R 10.1094/MPMI-22-8-1011 %0 Journal Article %J Invest Ophthalmol Vis Sci %D 2009 %T Mutation survey of known LCA genes and loci in the Saudi Arabian population. %A Yumei Li %A Wang, Hui %A Peng, Jianlan %A Richard A Gibbs %A Lewis, Richard Alan %A James R Lupski %A Mardon, Graeme %A Rui Chen %K Blindness %K Carrier Proteins %K cis-trans-Isomerases %K Consanguinity %K DNA Mutational Analysis %K Eye Proteins %K Female %K Genes %K Genotype %K Guanylate Cyclase %K Humans %K Male %K Membrane Proteins %K Microsatellite Repeats %K Mutation %K Nerve Tissue Proteins %K Pedigree %K Phenotype %K Polymerase Chain Reaction %K Receptors, Cell Surface %K Retinal Degeneration %K Saudi Arabia %X

PURPOSE: The purpose of this study was to perform a comprehensive survey of all known Leber congenital amaurosis (LCA) genes and loci in a collection of 37 consanguineous LCA families from Saudi Arabia.

METHODS: Direct PCR and sequencing were used to screen 13 known LCA genes (GUCY2D, CRX, RPE65, TULP1, AIPL1, CRB1, RPGRIP1, LRAT, RDH12, IMPDH1, CEP290, RD3, LCA5). In addition, families without mutations identified were further screened with STR markers around these 13 known LCA genes and two loci.

RESULTS: Disease-causing mutations were identified in nine of the 37 families: five in TULP1, two in CRB1, one in RPE65, and one in GUCY2D. Mutations in known genes only accounted for 24% of the Saudi families--much less than what has been observed in the European population (65%). Phenotype-genotype analysis was carried out to investigate the LCA disease penetrance for all families whose mutations identified. All identified mutations were found to segregate perfectly with the disease phenotype. On the other hand, severity of the disease varies for different patients carrying the same mutation and even within the same family. Furthermore, based on homozygosity mapping with both STR and SNP markers, one family is likely to map to the LCA3 locus.

CONCLUSIONS: These results underscore the importance of studying LCA disease families from different ethnic backgrounds to identify additional novel LCA disease genes. Furthermore, perfect segregation between mutation and disease indicates that LCA is fully penetrant. However, phenotypic variations among patients carrying the same mutation suggest that at least some of the variations in the clinical phenotype is due to modification from the genetic background, environment, or other factors.

%B Invest Ophthalmol Vis Sci %V 50 %P 1336-43 %8 2009 Mar %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/18936139?dopt=Abstract %R 10.1167/iovs.08-2589 %0 Journal Article %J Cancer Res %D 2007 %T Fine mapping and candidate gene analyses of pulmonary adenoma resistance 1, a major genetic determinant of mouse lung adenoma resistance. %A Wang, Min %A Zhang, Zhongqiu %A Zhang, Zhuo %A Vikis, Haris %A Yan, Ying %A Wang, Yian %A You, Ming %K Adenoma %K Animals %K Carrier Proteins %K Chromosome Mapping %K Female %K Genes, Tumor Suppressor %K Intracellular Signaling Peptides and Proteins %K Lung Neoplasms %K Male %K Mice %K Mice, Inbred A %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %X

Pulmonary adenoma resistance 1 (Par1) is a major genetic determinant of mouse lung adenoma resistance. Although Par1 was previously mapped to mouse chromosome 11 by conventional linkage analyses, its candidate region was broad and undefined. In our present study, we generated Par1 congenic mice using two mouse strains A/J (Par1/-) and Mus spretus (Par1/+). Analyzing these congenic mice enabled us to fine map the Par1 quantitative trait loci (QTL) into a 2.0-cM (2.2 Mb) chromosomal region between genetic marker D11Mit70 and the gene Hoxb9. We then conducted systematic candidate gene screening through nucleotide polymorphism and expression analyses. Genes showing differential lung tissue expression or carrying nonsynonymous single nucleotide polymorphisms were identified and discussed. In particular, we evaluated tumor suppressor gene Tob1 for its Par1 candidacy. Our findings have narrowed the Par1 QTL region and will greatly facilitate the identification of the major genetic determinant of mouse lung adenoma resistance.

%B Cancer Res %V 67 %P 2508-16 %8 2007 Mar 15 %G eng %N 6 %1 https://www.ncbi.nlm.nih.gov/pubmed/17363568?dopt=Abstract %R 10.1158/0008-5472.CAN-06-3157 %0 Journal Article %J Arterioscler Thromb Vasc Biol %D 2006 %T Consistent effects of genes involved in reverse cholesterol transport on plasma lipid and apolipoprotein levels in CARDIA participants. %A Klos, Kathy L E %A Sing, Charles F %A Eric Boerwinkle %A Hamon, Sara C %A Rea, Thomas J %A Clark, Andrew %A Fornage, Myriam %A Hixson, James E %K Adult %K Apolipoproteins %K Apolipoproteins A %K Apolipoproteins C %K Apolipoproteins E %K ATP Binding Cassette Transporter 1 %K ATP-Binding Cassette Transporters %K Biological Transport, Active %K Black People %K Carrier Proteins %K Cholesterol %K Cholesterol Ester Transfer Proteins %K Coronary Artery Disease %K Female %K Genetic Predisposition to Disease %K Genotype %K Glycoproteins %K Haplotypes %K Humans %K Lipids %K Male %K Polymorphism, Single Nucleotide %K White People %X

OBJECTIVE: To identify common variations in genes in the reverse cholesterol transport pathway with nongender-specific influence on plasma lipid and apolipoprotein levels.

METHODS AND RESULTS: An average of 5 single nucleotide polymorphisms (SNPs) were genotyped within each of 45 genomic regions (54 genes) in blacks (1131 females and 812 males) and whites (1102 females and 954 males) from the Coronary Artery Risk Development in Young Adults (CARDIA) study. SNPs and gene-based 3-SNP haplotypes were evaluated for their ability to predict variation in plasma apolipoproteins (apo) A-I and apoB, total cholesterol (TC), high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides (TG). We identified 14 SNPs in 6 candidate gene regions that explained statistically significant variation in the same trait in both genders of at least one race and with evidence of consistent genotype mean trend across gender within race. Haplotype analyses identified 9 candidate gene regions that explained statistically significant variation in one or both races.

CONCLUSIONS: Four gene regions, ABCA1, APOA1/C3/A4/A5, APOE/C1/C4/C2, and CETP, explained plasma lipoprotein variation most consistently across strata. Other gene regions that influence plasma lipid and apolipoprotein levels within race include CYP7A1, LPL, PPARA, SOAT1, and SREBF2.

%B Arterioscler Thromb Vasc Biol %V 26 %P 1828-36 %8 2006 Aug %G eng %N 8 %1 https://www.ncbi.nlm.nih.gov/pubmed/16763159?dopt=Abstract %R 10.1161/01.ATV.0000231523.19199.45 %0 Journal Article %J J Clin Microbiol %D 2005 %T Genetic diversity among type emm28 group A Streptococcus strains causing invasive infections and pharyngitis. %A Green, Nicole M %A Beres, Stephen B %A Graviss, Edward A %A Allison, James E %A McGeer, Allison J %A Vuopio-Varkila, Jaana %A LeFebvre, Rance B %A Musser, James M %K Antigens, Bacterial %K Bacterial Outer Membrane Proteins %K Carrier Proteins %K Chromosome Mapping %K Drug Resistance, Bacterial %K Genetic Variation %K Humans %K Macrolides %K Pharyngitis %K Prophages %K Streptococcal Infections %K Streptococcus pyogenes %K Virulence %X

Genome sequencing of group A Streptococcus (GAS) has revealed that prophages account for the vast majority of gene content differences between strains. Serotype M28 strains are a leading cause of pharyngitis and invasive infections, but little is known about genetic diversity present in natural populations of these organisms. To study this issue, population-based samples of 568 strains from Ontario, Canada; Finland; and Houston, Texas, were analyzed. Special attention was given to analysis of variation in prophage-encoded virulence gene content by a PCR-based method. Thirty and 29 distinct prophage-encoded virulence gene profiles were identified among pharyngitis and invasive infection isolates. Thirteen profiles, representing the majority of the strains, were shared between these two classes of isolates. Significant differences were observed in the frequency of occurrence of certain prophage toxin gene profiles and infection type. M28 strains are highly diverse in prophage-encoded virulence gene content and integration site, supporting the key concept that prophages are critical contributors to GAS genetic diversity and population biology. Nucleotide sequence variation in the emm gene (encodes M protein) was also examined. Only three allelic variants were identified in the hypervariable portion of the emm28 gene. All but one strain had the same inferred amino acid sequence in the first 100 amino acids of the mature M28 protein. In contrast, size differences in the emm28 gene and inferred protein due to variable numbers of C-terminal repeats were common. The presence of macrolide resistance genes (mefA, ermB, and ermTR) was analyzed by PCR, and less than 2% of the strains were positive.

%B J Clin Microbiol %V 43 %P 4083-91 %8 2005 Aug %G eng %N 8 %1 https://www.ncbi.nlm.nih.gov/pubmed/16081955?dopt=Abstract %R 10.1128/JCM.43.8.4083-4091.2005 %0 Journal Article %J Curr Atheroscler Rep %D 2005 %T Pharmacogenetics of response to statins: where do we stand? %A Maitland-van der Zee, Anke-Hilse %A Eric Boerwinkle %K Carrier Proteins %K Cholesterol Ester Transfer Proteins %K Cholesterol, LDL %K Coronary Artery Disease %K Glycoproteins %K Humans %K Hydroxymethylglutaryl-CoA Reductase Inhibitors %K Hypercholesterolemia %K Pharmacogenetics %K Polymorphism, Genetic %X

Cardiovascular disease is one of the leading causes of death, especially in developed countries. Blood cholesterol lowering by way of statin therapy is a common risk-lowering therapy. The risk reduction for coronary artery disease for patients using statins is 27%. These reductions, however, are average effects for all patients included in the trials. There is notable interindividual variation in response to statins, and the origins of this variation are poorly understood. Pharmacogenetics seeks to determine the role of genetic factors in variation of drug response. In patients with primary hypercholesterolemia, 23 studies have examined the effects of genetic polymorphisms at 20 different loci on the lipid response to statin treatment, and 18 studies examined genetic polymorphisms involved in the benefits of statin therapy in the prevention of cardiovascular disease. Even though many studies have been performed, few results have been replicated. It is our contention that larger sample sizes and consideration of multiple genes are needed in the field of pharmacogenetics of statin response.

%B Curr Atheroscler Rep %V 7 %P 204-8 %8 2005 May %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/15811254?dopt=Abstract %R 10.1007/s11883-005-0007-3 %0 Journal Article %J Am J Hum Genet %D 2003 %T Polymorphisms at the G72/G30 gene locus, on 13q33, are associated with bipolar disorder in two independent pedigree series. %A Hattori, Eiji %A Liu, Chunyu %A Badner, Judith A %A Bonner, Tom I %A Christian, Susan L %A Maheshwari, Manjula %A Detera-Wadleigh, Sevilla D %A Richard A Gibbs %A Gershon, Elliot S %K Alternative Splicing %K Bipolar Disorder %K Carrier Proteins %K Chromosomes, Human, Pair 13 %K DNA, Complementary %K Gene Frequency %K Genes %K Genetic Linkage %K Genetic Predisposition to Disease %K Haplotypes %K Humans %K Intracellular Signaling Peptides and Proteins %K Likelihood Functions %K Linkage Disequilibrium %K Molecular Sequence Data %K Pedigree %K Polymorphism, Single Nucleotide %K Sequence Analysis, DNA %X

Linkage evidence suggests that chromosome 13 (13q32-33) contains susceptibility genes for both bipolar disorder and schizophrenia. Recently, genes called "G72" and "G30" were identified, and polymorphisms of these overlapping genes were reported to be associated with schizophrenia. We studied two series of pedigrees with bipolar disorder: the Clinical Neurogenetics (CNG) pedigrees (in which linkage to illness had been previously reported at 13q32-33), with 83 samples from 22 multiplex families, and the National Institute of Mental Health (NIMH) Genetics Initiative pedigrees, with 474 samples from 152 families. Sixteen single-nucleotide polymorphisms (SNPs) were genotyped at and around the G72/G30 locus, which covered a 157-kb region encompassing the entire complementary DNA sequences of G72 and G30. We performed transmission/disequilibrium testing (TDT) and haplotype analysis, since a linkage-disequilibrium block was present at this gene locus. In the CNG and NIMH data sets, the results of global TDT of the entire haplotype set were significant and consistent (P=.0004 and P=.008, respectively). In the CNG series, the associated genotypes divided the families into those with linkage and those without linkage (partitioned by the linkage evidence). Analysis of the decay of haplotype sharing gave a location estimate that included G72/G30 in its 95% confidence interval. Although statistically significant association was not detected for individual SNPs in the NIMH data set, the same haplotype was consistently overtransmitted in both series. These data suggest that a susceptibility variant for bipolar illness exists in the vicinity of the G72/G30 genes. Taken together with the earlier report, this is the first demonstration of a novel gene(s), discovered through a positional approach, independently associated with both bipolar illness and schizophrenia.

%B Am J Hum Genet %V 72 %P 1131-40 %8 2003 May %G eng %N 5 %1 https://www.ncbi.nlm.nih.gov/pubmed/12647258?dopt=Abstract %R 10.1086/374822 %0 Journal Article %J Hum Mol Genet %D 1996 %T Duplication of a gene-rich cluster between 16p11.1 and Xq28: a novel pericentromeric-directed mechanism for paralogous genome evolution. %A Eichler, E E %A Lu, F %A Shen, Y %A Antonacci, R %A Jurecic, V %A Doggett, N A %A Moyzis, R K %A Baldini, A %A Richard A Gibbs %A Nelson, D L %K Animals %K Base Sequence %K Carrier Proteins %K Centromere %K Chromosome Mapping %K Chromosomes, Human, Pair 16 %K Cosmids %K Creatine %K Evolution, Molecular %K Exons %K Hominidae %K Humans %K Hylobates %K Membrane Proteins %K Membrane Transport Proteins %K Models, Genetic %K Molecular Sequence Data %K Multigene Family %K Proteins %K Repetitive Sequences, Nucleic Acid %K Sequence Analysis, DNA %K Sequence Homology, Nucleic Acid %K X Chromosome %X

We have identified a 26.5 kb gene-rich duplication shared by human Xq28 and 16p11.1. Complete comparative sequence analysis of cosmids from both loci has revealed identical Xq28 and 16p11.1 genomic structures for both the human creatine transporter gene (SLC6A8) and five exons of the CDM gene (DXS1357E). Overall nucleotide similarity within the duplication was found to be 94.6%, suggesting that this interchromosomal duplication occurred within recent evolutionary time (7-10 mya). Based on comparisons between genomic and cDNA sequence, both the Xq28 creatine transporter and DXS1357E genes are transcriptionally active. Predicted translation of exons and RT-PCR analysis reveal that chromosome 16 paralogs likely represent pseudogenes. Comparative fluorescent in situ hybridization (FISH) analyses of chromosomes from various primates indicate that this gene-rich segment has undergone several duplications. In gorilla and chimpanzee, multiple pericentromeric localizations on a variety of chromosomes were found using probes from the duplicated region. In other species, such as the orangutan and gibbon, FISH signals were only identified at the distal end of the X chromosome, suggesting that the Xq28 locus represents the ancestral copy. Sequencing of the 16p 11.1/Xq28 duplication breakpoints has revealed the presence of repetitive immunoglobulin-like CAGGG pentamer sequences at or near the paralogy boundaries. The mobilization and dispersal of this gene-rich 27 kb element to the pericentromeric regions of primate chromosomes defines an unprecedented form of recent genome evolution and a novel mechanism for the generation of genetic diversity among closely related species.

%B Hum Mol Genet %V 5 %P 899-912 %8 1996 Jul %G eng %N 7 %1 https://www.ncbi.nlm.nih.gov/pubmed/8817324?dopt=Abstract %R 10.1093/hmg/5.7.899 %0 Journal Article %J J Neuroimmunol %D 1995 %T Comparison of cell adhesion molecule expression between glioblastoma multiforme and autologous normal brain tissue. %A Marie-Claude Gingras %A Roussel, E %A Bruner, J M %A Branch, C D %A Moser, R P %K Antigens, CD %K Antigens, Tumor-Associated, Carbohydrate %K Brain Chemistry %K Brain Neoplasms %K Carrier Proteins %K CD58 Antigens %K Cell Adhesion Molecules %K Endothelium, Vascular %K Glioblastoma %K Humans %K Hyaluronan Receptors %K Immunohistochemistry %K Integrins %K Intercellular Adhesion Molecule-1 %K Membrane Glycoproteins %K Receptors, Cell Surface %K Receptors, Lymphocyte Homing %X

We investigated glioblastoma multiforme (GBM) for a pattern of consistent alterations in cell adhesion molecules (CAM) expression that might distinguish tumor from normal autologous brain tissue. We used frozen section immunohistochemistry with anti-CAM and computerized image analysis to quantify staining intensity which we expressed as relative intensity units (RIU). Our results showed that normal brain tissue generally did not express alpha 1 beta 1, intercellular CAM-1 (ICAM-1), and sialylated Lewisx, slightly expressed alpha 2, alpha 4, alpha 5, alpha 6 beta 1, alpha v beta 3, lymphocyte function-associated antigen-3 (LFA-3), Lewisx, sialylated LewisLewisx, had a good expression of alpha 3 beta 1 and CD44, and strongly expressed neural CAM (NCAM). GBM expressed alpha 2, alpha 3, alpha 5, alpha 6 beta 1, alpha v beta 3, ICAM-1, LFA-3, CD44, Lewisx, sialylated Lewisx, and sialylated LewisLewisx significantly higher (2-11-fold RIU) than normal brain tissue. ICAM-1 and LFA-3 were the most distinctive markers of GBM. The small blood vessel endothelial cells of the normal brain and the GBM showed a few differences. The tumor endothelium expression of alpha 2 beta 1, alpha 4 beta 1, and LFA-3 RIU appeared twice higher than in normal endothelium and alpha 6 beta 1 showed an average of 40% RIU decrease in comparison to normal. These results show that the expression of several CAM is consistently altered in GBM and its microvasculature when compared with autologous normal brain tissue.

%B J Neuroimmunol %V 57 %P 143-53 %8 1995 Mar %G eng %N 1-2 %1 https://www.ncbi.nlm.nih.gov/pubmed/7535788?dopt=Abstract %R 10.1016/0165-5728(94)00178-q