The goal of this project is to identify novel genes involved in human retinal disorders, a stated priority of the National Eye Institute. To accomplish this, additional genes whose mutations cause Leber congenital amaurosis (LCA), the most common hereditary cause of visual impairment in infants and children, will be identified by combining whole exome sequencing with genetic mapping. Mutations in known LCA genes account for about 63% of all cases in the European population, suggesting that many additional LCA genes remain to be identified. To identify additional LCA disease genes, we have collected 37 consanguineous families with recessive LCA from Saudi Arabia. Homozygosity mapping and known LCA disease gene sequencing suggests that 18 of these families carry novel mutations in multiple novel LCA disease loci. In addition, we have sequenced all 16 known LCA genes in a collection of over 600 patient samples and have identified 224 unrelated patients that likely carry mutations in novel LCA disease genes. Therefore, this collection represents a well characterized, rich resource for identifying new genes that can cause LCA. In this proposal, we will identify the underlying mutations in these patients using a combination of whole exome sequencing, bioinformatics, statistics, and functional studies.
Our Specific Aims are to: 1. Perform positional cloning of disease genes in consanguineous LCA families 2. Identify novel LCA genes by whole exome sequencing of a 300-patient cohort 3. Continued enrollment and mutation analysis of LCA families Discovery of novel LCA genes will assist the development of new diagnostic tools and treatments. In addition, since mutations in LCA disease genes also cause other retinal dystrophies, isolation of additional LCA disease genes will provide important insights into the molecular mechanisms underlying both LCA and retinal dystrophies in general.

Public Health Relevance

Description The goal of this research project is to use cutting edge genomic sequencing technology to identify novel genes that are involved in human Leber congenital amaurosis (LCA), the most common hereditary cause of visual impairment in infants and children. Currently, the cause of disease in about 35% of LCA patients remains unknown. Identification of novel LCA genes will provide the basis for accurate diagnosis as well as developing new treatment methods for the disease.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
3R01EY018571-06S1
Application #
8732067
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Shen, Grace L
Project Start
2007-12-01
Project End
2017-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
6
Fiscal Year
2013
Total Cost
$99,546
Indirect Cost
Name
Baylor College of Medicine
Department
Genetics
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Soens, Zachry T; Li, Yuanyuan; Zhao, Li et al. (2016) Hypomorphic mutations identified in the candidate Leber congenital amaurosis gene CLUAP1. Genet Med 18:1044-51
Tajiguli, Abulikemu; Xu, Mingchu; Fu, Qing et al. (2016) Next-generation sequencing-based molecular diagnosis of 12 inherited retinal disease probands of Uyghur ethnicity. Sci Rep 6:21384
Coppieters, Frauke; Ascari, Giulia; Dannhausen, Katharina et al. (2016) Isolated and Syndromic Retinal Dystrophy Caused by Biallelic Mutations in RCBTB1, a Gene Implicated in Ubiquitination. Am J Hum Genet 99:470-80
Zhao, Li; Chen, Yiyun; Bajaj, Amol Onkar et al. (2016) Integrative subcellular proteomic analysis allows accurate prediction of human disease-causing genes. Genome Res 26:660-9
Zhang, Qi; Xu, Mingchu; Verriotto, Jennifer D et al. (2016) Next-generation sequencing-based molecular diagnosis of 35 Hispanic retinitis pigmentosa probands. Sci Rep 6:32792
Xu, Mingchu; Yamada, Takeyuki; Sun, Zixi et al. (2016) Mutations in POMGNT1 cause non-syndromic retinitis pigmentosa. Hum Mol Genet 25:1479-88
Kmoch, S; Majewski, J; Ramamurthy, V et al. (2015) Mutations in PNPLA6 are linked to photoreceptor degeneration and various forms of childhood blindness. Nat Commun 6:5614
Zaneveld, Jacques; Siddiqui, Sorath; Li, Huajin et al. (2015) Comprehensive analysis of patients with Stargardt macular dystrophy reveals new genotype-phenotype correlations and unexpected diagnostic revisions. Genet Med 17:262-70
Xu, Mingchu; Gelowani, Violet; Eblimit, Aiden et al. (2015) ATF6 Is Mutated in Early Onset Photoreceptor Degeneration With Macular Involvement. Invest Ophthalmol Vis Sci 56:3889-95
Zhong, H; Eblimit, A; Moayedi, Y et al. (2015) AAV8(Y733F)-mediated gene therapy in a Spata7 knockout mouse model of Leber congenital amaurosis and retinitis pigmentosa. Gene Ther 22:619-27

Showing the most recent 10 out of 31 publications