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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 E Pennesi, Paul Yang, David Davis-Boozer, Hope Northrup, Vsevold V Gurevich, Rui Chen, Mingchu Xu, Yumei Li, David G Birch, Stephen P Daiger | Invest Ophthalmology Vis Science | 2017 May 1 | Vol 58(5) | pgs. 2774-2784 | doi: 10.1167/iovs.16-21341


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.


Retinitis pigmentosa (RP) is the most common form of inherited retinal disease (IRD) and has a prevalence of approximately 1 in 4000 worldwide.1 It is characterized by night blindness and progressive loss of peripheral vision, often leading to complete blindness. The presence of pigmentary deposits, attenuated retinal vessels, and changes to the ERG are typical clinical findings.2 RP is exceptionally heterogeneous, with more than 100 genetic causes already described (RetNet: https://sph.uth.edu/retnet/, in the public domain). Currently, mutations in 23 genes are known to cause dominant RP, 53 cause recessive RP, and 5 cause X-linked disease. At least 70 syndromic or systemic diseases include RP as a component. Variability in age of onset, secondary symptoms, rate of progression, and penetrance add to the complexity.


Our autosomal dominant RP (adRP) cohort, described previously,3 currently consists of 300 well-characterized families with evidence of an autosomal dominant form of disease. Likely pathogenic mutations have been identified in 226 of these families (75%). Of the 300 families, 195 (65%) have dominant mutations in known adRP genes, 25 (8%) have X-linked mutations, 3 (1%) have multiple segregating mutations, and 3 (1%) have dominant-acting mutations in genes previously associated with recessive diseases.


By a combination of exome sequencing and targeted-capture next-generation sequencing (NGS) of known IRD genes we identified a novel dominant-acting mutation in the SAG gene, a gene previously thought to cause only recessive disease.4,5 This mutation (NM_000541.4:c.440G>T; NP_000532.2:p.Cys147Phe) appears to descend from a common ancestor and accounts for 8 of the 74 families in the cohort in which mutations had not been identified previously.



 

References

  1. Daiger SP,, Bowne SJ,, Sullivan LS. Perspective on genes and mutations causing retinitis pigmentosa. Arch Ophthalmology. 2007; 125: 151–158.

  2. Heckenlively JR. Retinitis Pigmentosa. Philadelphia, PA: J.B. Lippincott; 1988.

  3. Sullivan LS,, Bowne SJ,, Birch DG,, et al. Prevalence of disease-causing mutations in families with autosomal dominant retinitis pigmentosa: a screen of known genes in 200 families. Invest Ophthalmology Vis Sci. 2006; 47: 3052–3064.

  4. Fuchs S,, Nakazawa M,, Maw M,, Tamai M,, Oguchi Y,, Gal A. A homozygous 1-base pair deletion in the arrestin gene is a frequent cause of Oguchi disease in Japanese. Nat Genet. 1995; 10: 360–362.

  5. Nakazawa M,, Wada Y,, Tamai M. Arrestin gene mutations in autosomal recessive retinitis pigmentosa. Arch Ophthalmology. 1998; 116: 498–501.

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