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Invest Ophthalmol Vis Sci. 2017 May 1;58(5):2774-2784. doi: 10.1167/iovs.16-21341.

A Novel Dominant Mutation in SAG, the Arrestin-1 Gene, Is a Common Cause of Retinitis Pigmentosa in Hispanic Families in the Southwestern United States.

Author information

1
Human Genetics Center, School of Public Health, The University of Texas Health Science Center, Houston, Texas, United States.
2
Nationwide Children's Hospital, Columbus, Ohio, United States.
3
Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan, United States.
4
Retina Foundation of the Southwest, Dallas, Texas, United States.
5
Ruiz Department of Ophthalmology and Visual Science, McGovern Medical School, The University of Texas Health Science Center, Houston, Texas, United States.
6
Casey Eye Institute, Oregon Health and Science University, Portland, Oregon, United States.
7
Department of Pediatrics, McGovern Medical School, The University of Texas Health Science Center, Houston, Texas, United States.
8
Vanderbilt University, Nashville, Tennessee, United States.
9
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States.
10
Human Genetics Center, School of Public Health, The University of Texas Health Science Center, Houston, Texas, United States 5Ruiz Department of Ophthalmology and Visual Science, McGovern Medical School, The University of Texas Health Science Center, Houston, Texas, United States.

Abstract

Purpose:

To identify the causes of autosomal dominant retinitis pigmentosa (adRP) in a cohort of families without mutations in known adRP genes and consequently to characterize a novel dominant-acting missense mutation in SAG.

Methods:

Patients underwent ophthalmologic testing and were screened for mutations using targeted-capture and whole-exome next-generation sequencing. Confirmation and additional screening were done by Sanger sequencing. Haplotypes segregating with the mutation were determined using short tandem repeat and single nucleotide variant polymorphisms. Genealogies were established by interviews of family members.

Results:

Eight families in a cohort of 300 adRP families, and four additional families, were found to have a novel heterozygous mutation in the SAG gene, c.440G>T; p.Cys147Phe. Patients exhibited symptoms of retinitis pigmentosa and none showed symptoms characteristic of Oguchi disease. All families are of Hispanic descent and most were ascertained in Texas or California. A single haplotype including the SAG mutation was identified in all families. The mutation dramatically alters a conserved amino acid, is extremely rare in global databases, and was not found in 4000+ exomes from Hispanic controls. Molecular modeling based on the crystal structure of bovine arrestin-1 predicts protein misfolding/instability.

Conclusions:

This is the first dominant-acting mutation identified in SAG, a founder mutation possibly originating in Mexico several centuries ago. The phenotype is clearly adRP and is distinct from the previously reported phenotypes of recessive null mutations, that is, Oguchi disease and recessive RP. The mutation accounts for 3% of the 300 families in the adRP Cohort and 36% of Hispanic families in this cohort.

PMID:
28549094
PMCID:
PMC5455168
DOI:
10.1167/iovs.16-21341
[Indexed for MEDLINE]
Free PMC Article

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