An ancestral mutation in SAG (S-antigen visual arrestin-1) is a common cause of autosomal dominant retinitis pigmentosa in Hispanics

Abstract

Purpose : To identify the cause 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, a gene previously associated with recessive Oguchi disease.

Methods : In a cohort of 300 adRP families, those without mutations identified earlier were screened for mutations using targeted-capture next generation sequencing (NGS) and whole-exome NGS. Following identification of a rare SAG variant in several cohort families, additional RP probands were screened for the variant. Pathogenicity was predicted using Variant Effect Predictor (VEP). Haplotypes segregating with the mutation were determined using STR and SNV polymorphisms. Genealogies were established by interviews of family members. Clinical details are in Birch, et al. ARVO, 2017.

Results : Eight adRP families in the cohort without known mutations were found to have an identical, heterozygous, missense mutation in the SAG gene, c.440G>T; p.Cys147Phe. Four more families with this mutation were identified in the additional probands tested. All twelve families are of Hispanic descent and most were ascertained in either Texas or California. A single haplotype including the SAG mutation was identified in each family, consistent with a common ancestral mutation. Interviews suggest the families originated in Mexico but have resided in the Southwest U.S. for many generations. The mutation is predicted to be pathogenic. The molecular effects of the mutation are likely to be protein misfolding/instability, with modeling based on the 2.8 Å bovine crystal structure of arrestin-1.

Conclusions : Recessive null mutations in SAG are known to cause Oguchi disease, a form of congenital stationary night blindness, and are a rare cause of recessive RP. This is the first dominant-acting mutation identified in SAG, likely to be a founder mutation originating in Mexico. The mutation accounts for 3% of our entire adRP cohort of 300 families and a much larger fraction (36%) of the Hispanic families in this cohort. It is extremely rare in global databases and was not found in 4,000+ exomes from Hispanic controls. Interviews and the ancestral haplotype suggest the mutation arose at least two centuries ago.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.