Mutations in the ABCA4 gene are responsible for a wide variety of retinal degeneration phenotypes, such as autosomal recessive Stargardt disease (STGD), cone-rod dystrophy (CRD) and retinitis pigmentosa (RP). Different combinations of """"""""mild"""""""", """"""""moderate"""""""", and """"""""severe"""""""" ABCA4 mutant alleles result in distinct phenotypes in a continuum of disease manifestations. Variation in the ABCA4 locus has emerged as the most prevalent cause of Mendelian retinal disease, with an estimated 1/20 people across all populations carrying a potential disease-associated variant in this gene. Clinical and allelic heterogeneity has substantially complicated genetic analyses of ABCA4-associated retinal disease. Direct sequencing of the entire ABCA4 open reading frame (ORF) currently detects up to 80% of the alleles, resulting in the identification of the 2 expected mutations in ~50% of patients, 1 mutation in 30%, while no disease-associated allele is found in the ABCA4 coding region in 20% patients. Since ABCA4 is the only known gene responsible for recessive STGD, it is clear that many disease- associated alleles must be located outside of the coding regions, especially in patients where 1 mutation is found in the ORF. The major goal of this proposal is to test the hypotheses that there are significant numbers of mutations in non-coding sequences of the ABCA4 genomic locus that contribute to ABCA4-associated disease load and that mutations in additional known and novel genes are responsible for the remainder of diseases with ABCA4-like phenotypes. To investigate these hypotheses, we will use our large clinical and genetic databases of sporadic and familial patients with ABCA4-associated diseases to determine all disease-associated variants in the entire ABCA4 locus on 1p21 by a step-by-step approach utilizing the next generation sequencing technologies and copy number variation (CNV) analyses. First, we will sequence the entire ABCA4 ORF in all patients with 1 mutation, followed by deep sequencing and CNV analyses of the entire ABCA4 genomic locus in these patients where no 2nd mutation will be found. After exhausting the ABCA4 locus analysis and confirming the variants by statistical and functional tests, we will determine what other genes are underlying ABCA4-like phenotypes in patients where no mutation is found in the ABCA4 locus by targeted resequencing of known loci, followed by full genome exome sequencing in selected families. The outcome of these studies will substantially aid in disease diagnosis, prognosis and will serve as a platform for selecting patients for emerging clinical trials geared to delay the onset, or arrest the progression, of ABCA4-associated diseases.

Public Health Relevance

Diseases caused by mutations in the ABCA4 gene represent a variety of autosomal recessive retinal degeneration phenotypes, including Stargardt disease (STGD), cone-rod dystrophy (CRD) and retinitis pigmentosa (RP);variation in the ABCA4 locus has emerged as the most prevalent cause of Mendelian retinal disease. Current mutation detection methods are able to identify 70-80% of all disease-causing alleles in the ABCA4 locus. Identification of all genetic variation in the ABCA4 locus by cutting-edge technologies, as suggested in this proposal, will substantially aid in disease diagnosis, prognosis and will serve as a platform for selecting patients for emerging clinical trials geared to delay the onset, or arrest the progression, of ABCA4- associated diseases.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY021163-02
Application #
8245692
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Shen, Grace L
Project Start
2011-04-01
Project End
2015-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
2
Fiscal Year
2012
Total Cost
$644,326
Indirect Cost
$127,807
Name
Columbia University (N.Y.)
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Ciccone, Lyam; Lee, Winston; Zernant, Jana et al. (2017) HYPERREFLECTIVE DEPOSITION IN THE BACKGROUND OF ADVANCED STARGARDT DISEASE. Retina :
Lee, Winston; Schuerch, Kaspar; Zernant, Jana et al. (2017) Genotypic spectrum and phenotype correlations of ABCA4-associated disease in patients of south Asian descent. Eur J Hum Genet 25:735-743
Xu, Mingchu; Xie, Yajing Angela; Abouzeid, Hana et al. (2017) Mutations in the Spliceosome Component CWC27 Cause Retinal Degeneration with or without Additional Developmental Anomalies. Am J Hum Genet 100:592-604
Zernant, Jana; Lee, Winston; Collison, Frederick T et al. (2017) Frequent hypomorphic alleles account for a significant fraction of ABCA4 disease and distinguish it from age-related macular degeneration. J Med Genet 54:404-412
Schuerch, Kaspar; Woods, Russell L; Lee, Winston et al. (2017) Quantifying Fundus Autofluorescence in Patients With Retinitis Pigmentosa. Invest Ophthalmol Vis Sci 58:1843-1855
Greenstein, Vivienne C; Nunez, Jason; Lee, Winston et al. (2017) A Comparison of En Face Optical Coherence Tomography and Fundus Autofluorescence in Stargardt Disease. Invest Ophthalmol Vis Sci 58:5227-5236
Yuan, Bo; Neira, Juanita; Gu, Shen et al. (2016) Nonrecurrent PMP22-RAI1 contiguous gene deletions arise from replication-based mechanisms and result in Smith-Magenis syndrome with evident peripheral neuropathy. Hum Genet 135:1161-74
Lee, Winston; Schuerch, Kaspar; Xie, Yajing et al. (2016) Simultaneous Expression of ABCA4 and GPR143 Mutations: A Complex Phenotypic Manifestation. Invest Ophthalmol Vis Sci 57:3409-15
Nõupuu, Kalev; Lee, Winston; Zernant, Jana et al. (2016) Recessive Stargardt disease phenocopying hydroxychloroquine retinopathy. Graefes Arch Clin Exp Ophthalmol 254:865-72
Lee, Winston; Xie, Yajing; Zernant, Jana et al. (2016) Complex inheritance of ABCA4 disease: four mutations in a family with multiple macular phenotypes. Hum Genet 135:9-19

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