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

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

Research output: Contribution to journalArticle

13 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2774-2784
Number of pages11
JournalInvestigative ophthalmology & visual science
Volume58
Issue number5
DOIs
StatePublished - May 1 2017

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

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    Sullivan, L. S., Bowne, S. J., Koboldt, D. C., Cadena, E. L., Heckenlively, J. R., Branham, K. E., Wheaton, D. H., Jones, K. D., Ruiz, R. S., Pennesi, M., Yang, P., Davis-Boozer, D., Northrup, H., Gurevich, V. V., Chen, R., Xu, M., Li, Y., Birch, D. G., & Daiger, S. P. (2017). 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. Investigative ophthalmology & visual science, 58(5), 2774-2784. https://doi.org/10.1167/iovs.16-21341