Mild Phenotypes of Gyrate Atrophy in a Heterozygous Carrier with One Variant Allele of OAT

Abstract

This study aimed to identify whether gyrate atrophy of the choroid and retina (GACR) heterozygous individuals have possible clinical manifestations and to explore the potential pathogenic mechanism. In this retrospective study, we surveyed a two-generation pedigree of an individual diagnosed with GACR. Two family members underwent ophthalmological, hematologic, and genetic tests. An arginine-restricted diet with vitamin B6 supplementation was implemented; clinical assessments were repeated every 3 months during follow-up. The relative OAT mRNA expression was determined using a real-time quantitative polymerase chain reaction. The 19-year-old compound heterozygous daughter (OAT: c.1186C>T; c.748C>T) had bilateral pathologic myopia, posterior staphyloma, chorioretinal atrophy, macular abnormalities, and elevated hematologic ornithine. The 54-year-old heterozygous mother (OAT: c.1186C>T) presented with bilateral pathologic myopia, asymmetric posterior staphyloma, retina and choroidal capillary layer atrophy, retinal pigment epithelium abnormalities, and mildly elevated hematologic ornithine. Compared to normal individuals, the daughter and mother had 29% and 46% relative OAT mRNA expression, respectively (p < 0.001). We believe that this is the first report of a carrier of one OAT variant allele exhibiting a mild phenotype, suggesting that family members should be aware of the possibility of clinical involvement in carriers with some autosomal recessive conditions. Additional data suggest that nonsense-mediated, decay-initiated mRNA degradation may cause GACR.

Keywords: OAT gene; allele; autosomal recessive; carrier; gyrate atrophy of the choroid and retina (GACR).

Figure 1

Identification of OAT variants in the family. (A): Pedigree of the family with gyrate atrophy with choroid and retina (GACR). Question marks indicate that the data were unavailable. (B): Sanger sequencing of the identified variants. Variant or wild-type nucleotides are indicated by red arrows. (C): Conservative analysis.

Figure 2

Ocular characteristics of F-II₁. (A,B): Ultra-widefield fundus images, including colour fundus and autofluorescence imaging. (C): Optical coherence tomography (OCT) revealed macular abnormalities (C1a,C2a) as well as retinal and choriocapillaris atrophy (C1b,C2b) in both eyes. An OCT B-scan of the left eye revealed deposits below the retinal pigment epithelium cells and choroidal atrophy (C2b). (D): Wide angio-OCT (OCTA) images of F-II₁ in the right (D1) and left eye (D2). (E): Electroretinography of F-II₁ cells and normal controls. Yellow arrows indicate retinal and choriocapillaris atrophy. White arrows indicate deposits below the retinal pigment epithelium cells.

Figure 3

Ocular characteristics of F-I₂. (A,B): Ultra-widefield fundus images include both colour fundus and autofluorescent images. (C): Optical coherence tomography (OCT) B-scan (Ca,b) and B-ultrasound (Ca’) of the left eye revealed inferior posterior staphyloma (PS) with retinoschisis. (D): OCT B-scan (Dc,f) and B-ultrasound (Dc’) of the right eye revealed a wide macular PS. OCT B-scan of the right eye revealed focal circular areas of retinal atrophy and choriocapillaris atrophy located in the region adjacent to the disc (Dc,d) and the supertemporal vascular arcade (De,f), with pigment epithelial detachment (PED) close to the retinal atrophy lesion (Df). Yellow arrows refer to focal circular areas of retinal atrophy and choriocapillaris atrophy. Yellow dotted squares indicate the site of PS. White arrows indicate PED.

Figure 4

Protein structure modelling and transcription analysis. (A): Three-dimensional structural model of the OAT protein. The truncated portion of the protein is coloured orange, and the mutants are shown as M1-b and M2-b. WT: wild-type. (B): Catalytic sites for substrate specificity in the OAT protein. Capital letters correspond to the abbreviations of different amino acid names, and numbers correspond to amino acid orders. (C): Relative OAT mRNA expression levels in peripheral blood (the whole blood samples) of the two family members and three normal controls. **: p < 0.01; *** p < 0.001. p < 0.05 was considered statistically significant. (D): Sanger sequencing of OAT cDNA reverse-transcribed from the mRNA of the whole blood samples on M1 (c.1186C>T) in the normal controls and two family members.