PUBLICATION
Hypomorphic mutations identified in the candidate Leber congenital amaurosis gene CLUAP1
- Authors
- Soens, Z.T., Li, Y., Zhao, L., Eblimit, A., Dharmat, R., Li, Y., Chen, Y., Naqeeb, M., Fajardo, N., Lopez, I., Sun, Z., Koenekoop, R.K., Chen, R.
- ID
- ZDB-PUB-160129-9
- Date
- 2016
- Source
- Genetics in medicine : official journal of the American College of Medical Genetics 18(10): 1044-51 (Journal)
- Registered Authors
- Sun, Zhaoxia
- Keywords
- none
- MeSH Terms
-
- Animals
- Antigens, Neoplasm/genetics*
- Child, Preschool
- Cilia/genetics*
- Cilia/metabolism
- Cilia/pathology
- Exome/genetics
- Female
- High-Throughput Nucleotide Sequencing
- Humans
- Leber Congenital Amaurosis/genetics*
- Leber Congenital Amaurosis/pathology
- Male
- Mutation
- Photoreceptor Cells/metabolism
- Photoreceptor Cells/pathology
- Retinal Degeneration/genetics*
- Retinal Degeneration/pathology
- Zebrafish
- PubMed
- 26820066 Full text @ Genet. Med.
Citation
Soens, Z.T., Li, Y., Zhao, L., Eblimit, A., Dharmat, R., Li, Y., Chen, Y., Naqeeb, M., Fajardo, N., Lopez, I., Sun, Z., Koenekoop, R.K., Chen, R. (2016) Hypomorphic mutations identified in the candidate Leber congenital amaurosis gene CLUAP1. Genetics in medicine : official journal of the American College of Medical Genetics. 18(10):1044-51.
Abstract
Purpose 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.
Methods 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.
Results 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.
Conclusion 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping