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. 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

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Free PMC article

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 et al. Invest Ophthalmol Vis Sci. .
Free PMC article

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.

Figures

Figure 1
Figure 1
Pedigrees of families included in this study. Males are represented by squares, females by circles, multiple children of unknown sex by diamonds. Patients affected with RP are represented by filled circles or squares; numbered individuals were typed for the SAG mutation.
Figure 2
Figure 2
Sequence alignment. Clustal alignment of arrestin sequences flanking SAG Cys147 from evolutionarily diverse members of the arrestin gene family. Conserved sequence of the structural 139-loop is shown in green, conservation of Cys147 in yellow. NP_000532.2:S-arrestin (Homo sapiens); NP_004032.2:beta-arrestin 1 isoform A (H. sapiens); NP_004304.1:beta-arrestin 2 isoform 1 (H. sapiens); NP_004303.2:arrestin-C (H. sapiens); NP_033144.1:S-arrestin (Mus musculus); NP_851343.1:S-arrestin (Bos taurus); NP_001081898.1:S-arrestin (Xenopus laevis); NP_956853.1:S-arrestin (Danio rerio); XP_011682264.1:beta-arrestin-1 isoform X1 (Strongylocentrotus purpuratus); NP_001041447:arrestin (Ciona intestinalis); NP_508183.1:probable beta-arrestin (Caenorhabditis elegans).
Figure 3
Figure 3
Cys147 in arrestin-1 structure. (A) Crystal structure of bovine arrestin-1 based on 1CF1. The C-tail is not shown as it is not visible in any arrestin crystal structure. Molecule A is shown, with β-strands colored light blue, α-helices red, and β-turns, green. Cys143 (homologue of human Cys147) is shown as a Corey-Pauling-Koltun model. Here and in (B), carbon atoms are shown in gray, nitrogen in blue, oxygen in red, and sulfur in yellow. Note that the side chain is facing inward and Cys143 is localized near the rhodopsin-binding finger loop and the 139-loop (also known as the middle loop) in the central crest of the molecule. (B) Intramolecular environment of Cys143 in bovine arrestin-1. Note tight packing around relatively small side chain of Cys143. Replacement of this cysteine with much bulkier phenylalanine creates clashes with indicated neighboring residues Leu132, Val247, Tyr255, and Ile323 (corresponding to residues Leu136, Val251, Tyr259, and Ile327 in highly homologous human arrestin-1).
Figure 4
Figure 4
Haplotype surrounding the SAG Cys147Phe mutation. Seventeen single-nucleotide polymorphisms (SNPs) and four STRs were typed in all available members of the 12 families with the SAG Cys147Phe mutation. Genotypes were examined and the disease haplotype determined in as many families as possible. All individuals carried a haplotype or corresponding genotype consistent with a founder mutation occurring several generations ago. The minimal haplotype region was determined to be 1.31 Mb and located between SNPs rs181158151 and rs950834.
Figure 5
Figure 5
Fundus montages and OCTs of representative patients with the SAG Cys147Phe mutation. (A, C) Patient RFS516-11005, a 48-year-old male with adRP. Retinal thinning, bone-spicule pigmentation and patches of atrophy are present in a midperipheral ring. A horizontal midline OCT scan (C) shows an intact ellipsoid zone in the central macula but extensive degeneration outside the arcades. The arrows indicate hyperreflective spots, which are seen in all retinal layers. (B, D) Patient RFS 138-11896, a 54-year-old male with adRP. Extensive atrophy is present throughout the periphery. A horizontal midline OCT scan (D) shows an intact ellipsoid zone in the central macula. Immediately peripheral to the central macula there is loss of the photoreceptor layer, including the nuclear layer, and extensive disruption of the RPE.

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