%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 PLoS Genet %D 2018 %T Mutation in the intracellular chloride channel CLCC1 associated with autosomal recessive retinitis pigmentosa. %A Li, Lin %A Jiao, Xiaodong %A D'Atri, Ilaria %A Ono, Fumihito %A Nelson, Ralph %A Chan, Chi-Chao %A Nakaya, Naoki %A Ma, Zhiwei %A Ma, Yan %A Cai, Xiaoying %A Zhang, Longhua %A Lin, Siying %A Hameed, Abdul %A Chioza, Barry A %A Hardy, Holly %A Arno, Gavin %A Hull, Sarah %A Khan, Muhammad Imran %A Fasham, James %A Harlalka, Gaurav V %A Michaelides, Michel %A Moore, Anthony T %A Coban Akdemir, Zeynep Hande %A Jhangiani, Shalini %A James R Lupski %A Cremers, Frans P M %A Qamar, Raheel %A Salman, Ahmed %A Chilton, John %A Self, Jay %A Ayyagari, Radha %A Kabir, Firoz %A Naeem, Muhammad Asif %A Ali, Muhammad %A Akram, Javed %A Sieving, Paul A %A Riazuddin, Sheikh %A Baple, Emma L %A Riazuddin, S Amer %A Crosby, Andrew H %A Hejtmancik, J Fielding %K Animals %K Asian People %K Cell Line %K Chloride Channels %K Cytoplasm %K Eye Proteins %K HEK293 Cells %K Homozygote %K Humans %K Mice %K Mice, Knockout %K Mutation, Missense %K Pakistan %K Retina %K Retinal Cone Photoreceptor Cells %K Retinal Rod Photoreceptor Cells %K Retinitis Pigmentosa %K Zebrafish %X

We identified a homozygous missense alteration (c.75C>A, p.D25E) in CLCC1, encoding a presumptive intracellular chloride channel highly expressed in the retina, associated with autosomal recessive retinitis pigmentosa (arRP) in eight consanguineous families of Pakistani descent. The p.D25E alteration decreased CLCC1 channel function accompanied by accumulation of mutant protein in granules within the ER lumen, while siRNA knockdown of CLCC1 mRNA induced apoptosis in cultured ARPE-19 cells. TALEN KO in zebrafish was lethal 11 days post fertilization. The depressed electroretinogram (ERG) cone response and cone spectral sensitivity of 5 dpf KO zebrafish and reduced eye size, retinal thickness, and expression of rod and cone opsins could be rescued by injection of wild type CLCC1 mRNA. Clcc1+/- KO mice showed decreased ERGs and photoreceptor number. Together these results strongly suggest that intracellular chloride transport by CLCC1 is a critical process in maintaining retinal integrity, and CLCC1 is crucial for survival and function of retinal cells.

%B PLoS Genet %V 14 %P e1007504 %8 2018 Aug %G eng %N 8 %1 https://www.ncbi.nlm.nih.gov/pubmed/30157172?dopt=Abstract %R 10.1371/journal.pgen.1007504 %0 Journal Article %J JAMA Ophthalmol %D 2016 %T Molecular and Clinical Findings in Patients With Knobloch Syndrome. %A Hull, Sarah %A Arno, Gavin %A Ku, Cristy A %A Ge, Zhongqi %A Waseem, Naushin %A Chandra, Aman %A Webster, Andrew R %A Robson, Anthony G %A Michaelides, Michel %A Weleber, Richard G %A Davagnanam, Indran %A Rui Chen %A Holder, Graham E %A Pennesi, Mark E %A Moore, Anthony T %K Adolescent %K Adult %K Child %K Child, Preschool %K Collagen Type VIII %K Collagen Type XVIII %K DNA Mutational Analysis %K Electroretinography %K Encephalocele %K Exfoliation Syndrome %K Exons %K Female %K Glaucoma, Open-Angle %K Humans %K Magnetic Resonance Imaging %K Male %K Molecular Biology %K Mutation %K Myopia, Degenerative %K Pedigree %K Photoreceptor Cells, Vertebrate %K Polymerase Chain Reaction %K Retinal Degeneration %K Retinal Detachment %K Vision Disorders %K Young Adult %X

IMPORTANCE: Knobloch syndrome is a rare, recessively inherited disorder classically characterized by high myopia, retinal detachment, and occipital encephalocele, but it is now known to have an increasingly variable phenotype. There is a lack of reported electrophysiologic data, and some key clinical features have yet to be described.

OBJECTIVE: To expand on current clinical, electrophysiologic, and molecular genetic findings in Knobloch syndrome.

DESIGN, SETTING, AND PARTICIPANTS: Twelve patients from 7 families underwent full ophthalmic examination and retinal imaging. Further investigations included electroretinography and neuroradiologic imaging. Bidirectional Sanger sequencing of COL18A1 was performed with segregation on available relatives. The study was conducted from July 4, 2013, to October 5, 2015. Data analysis was performed from May 20, 2014, to November 3, 2015.

MAIN OUTCOMES AND MEASURES: Results of ophthalmic and neuroradiologic assessment and sequence analysis of COL18A1.

RESULTS: Of the 12 patients (6 males; mean age at last review, 16 years [range, 2-38 years]), all had high myopia in at least 1 eye and severely reduced vision. A sibling pair had unilateral high myopia in their right eyes and near emmetropia in their left eyes from infancy. Anterior segment abnormalities included absent iris crypts, iris transillumination, lens subluxation, and cataract. Two patients with iris transillumination had glaucoma. Fundus characteristics included abnormal collapsed vitreous, macular atrophy, and a tesselated fundus. Five patients had previous retinal detachment. Electroretinography revealed a cone-rod pattern of dysfunction in 8 patients, was severely reduced or undetectable in 2 patients, and demonstrated cone-rod dysfunction in 1 eye with undetectable responses in the other eye in 2 patients. Radiologic imaging demonstrated occipital encephalocele or meningocele in 3 patients, occipital skull defects in 4 patients, minor occipital changes in 2 patients, and no abnormalities in 2 patients. Cutaneous scalp changes were present in 5 patients. Systemic associations were identified in 8 patients, including learning difficulties, epilepsy, and congenital renal abnormalities. Biallelic mutations including 2 likely novel mutations in COL18A1, were identified in 6 families that were consistent with autosomal recessive inheritance with a single mutation identified in a family with 2 affected children.

CONCLUSIONS AND RELEVANCE: This report describes new features in patients with Knobloch syndrome, including pigment dispersion syndrome and glaucoma as well as cone-rod dysfunction on electroretinography. Two patients had normal neuroradiologic findings, emphasizing that some affected individuals have isolated ocular disease. Awareness of the ocular phenotype may aid early diagnosis, appropriate genetic counseling, and monitoring for potential complications.

%B JAMA Ophthalmol %V 134 %P 753-62 %8 2016 Jul 01 %G eng %N 7 %1 https://www.ncbi.nlm.nih.gov/pubmed/27259167?dopt=Abstract %R 10.1001/jamaophthalmol.2016.1073 %0 Journal Article %J Am J Hum Genet %D 2016 %T Mutations in REEP6 Cause Autosomal-Recessive Retinitis Pigmentosa. %A Arno, Gavin %A Agrawal, Smriti A %A Eblimit, Aiden %A Bellingham, James %A Xu, Mingchu %A Wang, Feng %A Chakarova, Christina %A Parfitt, David A %A Lane, Amelia %A Burgoyne, Thomas %A Hull, Sarah %A Carss, Keren J %A Fiorentino, Alessia %A Hayes, Matthew J %A Munro, Peter M %A Nicols, Ralph %A Pontikos, Nikolas %A Holder, Graham E %A Asomugha, Chinwe %A Raymond, F Lucy %A Moore, Anthony T %A Plagnol, Vincent %A Michaelides, Michel %A Hardcastle, Alison J %A Li, Yumei %A Cukras, Catherine %A Webster, Andrew R %A Cheetham, Michael E %A Chen, Rui %K Adolescent %K Alleles %K Animals %K Child %K Child, Preschool %K Eye Proteins %K Female %K Genes, Recessive %K Humans %K Induced Pluripotent Stem Cells %K Male %K Membrane Proteins %K Membrane Transport Proteins %K Mice %K Mutation %K Mutation, Missense %K Phenotype %K Photoreceptor Cells, Vertebrate %K Retinitis Pigmentosa %K Young Adult %X

Retinitis pigmentosa (RP) is the most frequent form of inherited retinal dystrophy. RP is genetically heterogeneous and the genes identified to date encode proteins involved in a wide range of functional pathways, including photoreceptor development, phototransduction, the retinoid cycle, cilia, and outer segment development. Here we report the identification of biallelic mutations in Receptor Expression Enhancer Protein 6 (REEP6) in seven individuals with autosomal-recessive RP from five unrelated families. REEP6 is a member of the REEP/Yop1 family of proteins that influence the structure of the endoplasmic reticulum but is relatively unstudied. The six variants identified include three frameshift variants, two missense variants, and a genomic rearrangement that disrupts exon 1. Human 3D organoid optic cups were used to investigate REEP6 expression and confirmed the expression of a retina-specific isoform REEP6.1, which is specifically affected by one of the frameshift mutations. Expression of the two missense variants (c.383C>T [p.Pro128Leu] and c.404T>C [p.Leu135Pro]) and the REEP6.1 frameshift mutant in cultured cells suggest that these changes destabilize the protein. Furthermore, CRISPR-Cas9-mediated gene editing was used to produce Reep6 knock-in mice with the p.Leu135Pro RP-associated variant identified in one RP-affected individual. The homozygous knock-in mice mimic the clinical phenotypes of RP, including progressive photoreceptor degeneration and dysfunction of the rod photoreceptors. Therefore, our study implicates REEP6 in retinal homeostasis and highlights a pathway previously uncharacterized in retinal dystrophy.

%B Am J Hum Genet %V 99 %P 1305-1315 %8 2016 Dec 01 %G eng %N 6 %1 https://www.ncbi.nlm.nih.gov/pubmed/27889058?dopt=Abstract %R 10.1016/j.ajhg.2016.10.008