%0 Journal Article %J Dev Cell %D 2022 %T Loss of non-motor kinesin KIF26A causes congenital brain malformations via dysregulated neuronal migration and axonal growth as well as apoptosis. %A Qian, Xuyu %A DeGennaro, Ellen M %A Talukdar, Maya %A Akula, Shyam K %A Lai, Abbe %A Shao, Diane D %A Gonzalez, Dilenny %A Marciano, Jack H %A Smith, Richard S %A Hylton, Norma K %A Yang, Edward %A Bazan, J Fernando %A Barrett, Lee %A Yeh, Rebecca C %A Hill, R Sean %A Beck, Samantha G %A Otani, Aoi %A Angad, Jolly %A Mitani, Tadahiro %A Posey, Jennifer E %A Pehlivan, Davut %A Calame, Daniel %A Aydin, Hatip %A Yesilbas, Osman %A Parks, Kendall C %A Argilli, Emanuela %A England, Eleina %A Im, Kiho %A Taranath, Ajay %A Scott, Hamish S %A Barnett, Christopher P %A Arts, Peer %A Sherr, Elliott H %A James R Lupski %A Walsh, Christopher A %K Animals %K Apoptosis %K Brain %K Focal Adhesion Protein-Tyrosine Kinases %K Humans %K Kinesins %K Mice %K Neurons %X

Kinesins are canonical molecular motors but can also function as modulators of intracellular signaling. KIF26A, an unconventional kinesin that lacks motor activity, inhibits growth-factor-receptor-bound protein 2 (GRB2)- and focal adhesion kinase (FAK)-dependent signal transduction, but its functions in the brain have not been characterized. We report a patient cohort with biallelic loss-of-function variants in KIF26A, exhibiting a spectrum of congenital brain malformations. In the developing brain, KIF26A is preferentially expressed during early- and mid-gestation in excitatory neurons. Combining mice and human iPSC-derived organoid models, we discovered that loss of KIF26A causes excitatory neuron-specific defects in radial migration, localization, dendritic and axonal growth, and apoptosis, offering a convincing explanation of the disease etiology in patients. Single-cell RNA sequencing in KIF26A knockout organoids revealed transcriptional changes in MAPK, MYC, and E2F pathways. Our findings illustrate the pathogenesis of KIF26A loss-of-function variants and identify the surprising versatility of this non-motor kinesin.

%B Dev Cell %V 57 %P 2381-2396.e13 %8 2022 Oct 24 %G eng %N 20 %1 https://www.ncbi.nlm.nih.gov/pubmed/36228617?dopt=Abstract %R 10.1016/j.devcel.2022.09.011 %0 Journal Article %J Mol Psychiatry %D 2021 %T RCL1 copy number variants are associated with a range of neuropsychiatric phenotypes. %A Brownstein, Catherine A %A Smith, Richard S %A Rodan, Lance H %A Gorman, Mark P %A Hojlo, Margaret A %A Garvey, Emily A %A Li, Jianqiao %A Cabral, Kristin %A Bowen, Joshua J %A Rao, Abhijit S %A Genetti, Casie A %A Carroll, Devon %A Deaso, Emma A %A Agrawal, Pankaj B %A Rosenfeld, Jill A %A Bi, Weimin %A Howe, Jennifer %A Stavropoulos, Dimitri J %A Hansen, Adam W %A Hamoda, Hesham M %A Pinard, Ferne %A Caracansi, Annmarie %A Walsh, Christopher A %A D'Angelo, Eugene J %A Beggs, Alan H %A Zarrei, Mehdi %A Richard A Gibbs %A Scherer, Stephen W %A Glahn, David C %A Gonzalez-Heydrich, Joseph %K Adolescent %K DNA Copy Number Variations %K Exome Sequencing %K Humans %K Male %K Mutation %K Phenotype %X

Mendelian and early-onset severe psychiatric phenotypes often involve genetic variants having a large effect, offering opportunities for genetic discoveries and early therapeutic interventions. Here, the index case is an 18-year-old boy, who at 14 years of age had a decline in cognitive functioning over the course of a year and subsequently presented with catatonia, auditory and visual hallucinations, paranoia, aggression, mood dysregulation, and disorganized thoughts. Exome sequencing revealed a stop-gain mutation in RCL1 (NM_005772.4:c.370 C > T, p.Gln124Ter), encoding an RNA 3'-terminal phosphate cyclase-like protein that is highly conserved across eukaryotic species. Subsequent investigations across two academic medical centers identified eleven additional cases of RCL1 copy number variations (CNVs) with varying neurodevelopmental or psychiatric phenotypes. These findings suggest that dosage variation of RCL1 contributes to a range of neurological and clinical phenotypes.

%B Mol Psychiatry %V 26 %P 1706-1718 %8 2021 May %G eng %N 5 %1 https://www.ncbi.nlm.nih.gov/pubmed/33597717?dopt=Abstract %R 10.1038/s41380-021-01035-y %0 Journal Article %J Am J Hum Genet %D 2019 %T Homozygous Missense Variants in NTNG2, Encoding a Presynaptic Netrin-G2 Adhesion Protein, Lead to a Distinct Neurodevelopmental Disorder. %A Dias, Caroline M %A Punetha, Jaya %A Zheng, Céline %A Mazaheri, Neda %A Rad, Abolfazl %A Efthymiou, Stephanie %A Petersen, Andrea %A Dehghani, Mohammadreza %A Pehlivan, Davut %A Partlow, Jennifer N %A Posey, Jennifer E %A Salpietro, Vincenzo %A Gezdirici, Alper %A Malamiri, Reza Azizi %A Al Menabawy, Nihal M %A Selim, Laila A %A Vahidi Mehrjardi, Mohammad Yahya %A Banu, Selina %A Polla, Daniel L %A Yang, Edward %A Rezazadeh Varaghchi, Jamileh %A Mitani, Tadahiro %A van Beusekom, Ellen %A Najafi, Maryam %A Sedaghat, Alireza %A Keller-Ramey, Jennifer %A Durham, Leslie %A Coban-Akdemir, Zeynep %A Karaca, Ender %A Orlova, Valeria %A Schaeken, Lieke L M %A Sherafat, Amir %A Jhangiani, Shalini N %A Stanley, Valentina %A Shariati, Gholamreza %A Galehdari, Hamid %A Gleeson, Joseph G %A Walsh, Christopher A %A James R Lupski %A Seiradake, Elena %A Houlden, Henry %A van Bokhoven, Hans %A Maroofian, Reza %K Adolescent %K Adult %K Child %K Child, Preschool %K Exome %K Exome Sequencing %K Female %K GPI-Linked Proteins %K Homozygote %K Humans %K Intellectual Disability %K Male %K Mutation, Missense %K Netrins %K Neurodevelopmental Disorders %K Pedigree %K Young Adult %X

NTNG2 encodes netrin-G2, a membrane-anchored protein implicated in the molecular organization of neuronal circuitry and synaptic organization and diversification in vertebrates. In this study, through a combination of exome sequencing and autozygosity mapping, we have identified 16 individuals (from seven unrelated families) with ultra-rare homozygous missense variants in NTNG2; these individuals present with shared features of a neurodevelopmental disorder consisting of global developmental delay, severe to profound intellectual disability, muscle weakness and abnormal tone, autistic features, behavioral abnormalities, and variable dysmorphisms. The variants disrupt highly conserved residues across the protein. Functional experiments, including in silico analysis of the protein structure, in vitro assessment of cell surface expression, and in vitro knockdown, revealed potential mechanisms of pathogenicity of the variants, including loss of protein function and decreased neurite outgrowth. Our data indicate that appropriate expression of NTNG2 plays an important role in neurotypical development.

%B Am J Hum Genet %V 105 %P 1048-1056 %8 2019 Nov 07 %G eng %N 5 %1 https://www.ncbi.nlm.nih.gov/pubmed/31668703?dopt=Abstract %R 10.1016/j.ajhg.2019.09.025 %0 Journal Article %J Science %D 2007 %T Comment on "Ongoing adaptive evolution of ASPM, a brain size determinant in Homo sapiens". %A Fuli Yu %A Hill, R Sean %A Schaffner, Stephen F %A Sabeti, Pardis C %A Wang, Eric T %A Mignault, Andre A %A Ferland, Russell J %A Moyzis, Robert K %A Walsh, Christopher A %A Reich, David %K Adaptation, Biological %K Asian People %K Biological Evolution %K Black People %K Brain %K Gene Frequency %K Haplotypes %K Humans %K Nerve Tissue Proteins %K Polymorphism, Single Nucleotide %K Recombination, Genetic %K Selection, Genetic %K Sequence Analysis, DNA %K Time %K White People %X

Mekel-Bobrov et al. (Reports, 9 September 2005, p. 1720) suggested that ASPM, a gene associated with microcephaly, underwent natural selection within the last 500 to 14,100 years. Their analyses based on comparison with computer simulations indicated that ASPM had an unusual pattern of variation. However, when we compare ASPM empirically to a large number of other loci, its variation is not unusual and does not support selection.

%B Science %V 316 %P 370 %8 2007 Apr 20 %G eng %N 5823 %1 https://www.ncbi.nlm.nih.gov/pubmed/17446375?dopt=Abstract %R 10.1126/science.316.5823.370a