title: Hypomorphic mutations identified in the candidate Leber congenital amaurosis gene CLUAP1.
abstract: Leber congenital amaurosis (LCA) is an early-onset form of retinal degeneration. Six of the 22 known LCA genes encode photoreceptor ciliary proteins. Despite the identification of 22 LCA genes, the genetic basis of ~30% of LCA patients remains unknown. We sought to investigate the cause of disease in the remaining 30% by examining cilia-associated genes.
  
  
  
  Whole-exome sequencing was performed on an LCA cohort of 212 unsolved probands previously screened for mutations in known retinal-disease genes. Immunohistochemistry using mouse retinas was used to confirm protein localization and zebrafish were used to perform rescue experiments.
  
  
  
  A homozygous nonsynonymous mutation was found in a single proband in CLUAP1, a gene required for ciliogenesis and cilia maintenance. Cluap1 knockout zebrafish exhibit photoreceptor cell death as early as 5 days after fertilization, and rescue experiments revealed that our proband's mutation is significantly hypomorphic.
  
  
  
  Consistent with the knowledge that CLUAP1 plays an important role in cilia function and that cilia are critical to photoreceptor function, our results indicate that hypomorphic mutations in CLUAP1 can result in dysfunctional photoreceptors without systemic abnormalities. This is the first report linking mutations in CLUAP1 to human disease and establishes CLUAP1 as a candidate LCA gene.Genet Med 18 10, 1044-1051.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.|Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Zachry T
authors.identifier: 0000-0003-4701-4867
authors.initials: ZT
authors.lastname: Soens
authors.affiliation: Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Yuanyuan
authors.identifier: 0000-0003-4227-8628
authors.initials: Y
authors.lastname: Li
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.|Department of Structural and Computational Biology & Molecular Biophysics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.|Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Aiden
authors.identifier: 0000-0002-7743-6385
authors.initials: A
authors.lastname: Eblimit
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.|Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Rachayata
authors.identifier: 0000-0001-6969-4459
authors.initials: R
authors.lastname: Dharmat
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.|Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Yumei
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.|Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Yiyun
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Ophthalmology, Um Al Qura University Medical School, Makkah, Saudi Arabia.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Naqeeb
authors.affiliation: McGill Ocular Genetics Laboratory and Centre, Department of Ophthalmology, McGill University Health Centre, Montreal, Quebec, Canada.|Department of Paediatric Surgery, McGill University Health Centre, Montreal, Quebec, Canada.|Department of Human Genetics, McGill University Health Centre, Montreal, Quebec, Canada.
authors.forename: Norma
authors.initials: N
authors.lastname: Fajardo
authors.affiliation: McGill Ocular Genetics Laboratory and Centre, Department of Ophthalmology, McGill University Health Centre, Montreal, Quebec, Canada.|Department of Paediatric Surgery, McGill University Health Centre, Montreal, Quebec, Canada.|Department of Human Genetics, McGill University Health Centre, Montreal, Quebec, Canada.
authors.forename: Irma
authors.initials: I
authors.lastname: Lopez
authors.affiliation: Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Zhaoxia
authors.initials: Z
authors.lastname: Sun
authors.affiliation: McGill Ocular Genetics Laboratory and Centre, Department of Ophthalmology, McGill University Health Centre, Montreal, Quebec, Canada.|Department of Paediatric Surgery, McGill University Health Centre, Montreal, Quebec, Canada.|Department of Human Genetics, McGill University Health Centre, Montreal, Quebec, Canada.
authors.forename: Robert K
authors.initials: RK
authors.lastname: Koenekoop
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.|Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.|Department of Structural and Computational Biology & Molecular Biophysics, Baylor College of Medicine, Houston, Texas, USA.|Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas, USA.|Program of Developmental Biology, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Chen
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics*; D002675:Child, Preschool; D002923:Cilia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D059472:Exome / Q000235:genetics; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D057130:Leber Congenital Amaurosis / Q000235:genetics* / Q000473:pathology; D008297:Male; D009154:Mutation; D010786:Photoreceptor Cells / Q000378:metabolism / Q000473:pathology; D012162:Retinal Degeneration / Q000235:genetics* / Q000473:pathology; D015027:Zebrafish
chemical_list: D000951:Antigens, Neoplasm; C518614:CLUAP1 protein, human
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