Lori S. Sullivan 1 , Sara J. Bowne 1 , Daniel C. Koboldt 2 , Elizabeth L. Cadena 1 , John R. Heckenlively 3 , Kari E. Branham 3 , Dianna H. Wheaton 4 , Kaylie D. Jones 4 , Richard S. Ruiz 5 , Mark E. Pennesi 6 , Paul Yang 6 , David Davis-Boozer 6 , Hope Northrup 7 , Vsevold V. Gurevich 8 , Rui Chen 9 , Mingchu Xu 9 , Yumei Li 9 , David G. Birch 4 , Stephen P. Daiger 1 , 5
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.
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.
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.
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.