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GUCA1A mutation causes maculopathy in a five-generation family with a wide spectrum of severity.

ABSTRACT: The aim of this study was to investigate the genetic basis and pathogenic mechanism of variable maculopathies, ranging from mild photoreceptor degeneration to central areolar choroidal dystrophy, in a five-generation family.Clinical characterizations, whole-exome sequencing, and genome-wide linkage analysis were carried out on the family. Zebrafish models were used to investigate the pathogenesis of GUCA1A mutations.A novel mutation, GUCA1A p.R120L, was identified in the family and predicted to alter the tertiary structure of guanylyl cyclase-activating protein 1, a photoreceptor-expressed protein encoded by the GUCA1A gene. The mutation was shown in zebrafish to cause significant disruptions in photoreceptors and retinal pigment epithelium, together with atrophies of retinal vessels and choriocapillaris. Those phenotypes could not be fully rescued by exogenous wild-type GUCA1A, suggesting a likely gain-of-function mechanism for p.R120L. GUCA1A p.D100E, another mutation previously implicated in cone dystrophy, also impaired the retinal pigment epithelium and photoreceptors in zebrafish, but probably via a dominant negative effect.We conclude that GUCA1A mutations could cause significant variability in maculopathies, including central areolar choroidal dystrophy, which represents a severe pattern of maculopathy. The diverse pathogenic modes of GUCA1A mutations may explain the phenotypic diversities.Genet Med advance online publication 26 January 2017.

SUBMITTER: Chen X

PROVIDER: S-EPMC5548935 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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GUCA1A mutation causes maculopathy in a five-generation family with a wide spectrum of severity.

Chen Xue X Sheng Xunlun X Zhuang Wenjuan W Sun Xiantao X Liu Guohua G Shi Xun X Huang Guofu G Mei Yan Y Li Yingjie Y Pan Xinyuan X Liu Yani Y Li Zili Z Zhao Qingshun Q Yan Biao B Zhao Chen C

Genetics in medicine : official journal of the American College of Medical Genetics 20170126 8

<h4>Purpose</h4>The aim of this study was to investigate the genetic basis and pathogenic mechanism of variable maculopathies, ranging from mild photoreceptor degeneration to central areolar choroidal dystrophy, in a five-generation family.<h4>Methods</h4>Clinical characterizations, whole-exome sequencing, and genome-wide linkage analysis were carried out on the family. Zebrafish models were used to investigate the pathogenesis of GUCA1A mutations.<h4>Results</h4>A novel mutation, GUCA1A p.R120L ...[more]

PMID: 28125083

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Project description:BACKGROUND:Spondyloepiphyseal dysplasia tarda (SEDT) is a rare X-linked recessive inherited osteochondrodysplasia caused by mutations in the TRAPPC2 gene. It is clinically characterized by disproportionate short stature and early onset of degenerative osteoarthritis. Clinical diagnosis can be challenging due to the late-onset of the disease and lack of systemic metabolic abnomalites. Genetic diagnosis is critical in both early diagnosis and management of the disease. Here we reported a five-generation Chinese SEDT family and described the novel molecular findings. METHODS:Detailed family history and clinical data were collected. Genomic DNA was extracted from venous blood samples of family members. The exons of genes known to be associated with skeletal disorders were captured and deep sequenced. Variants were annotated by ANNOVAR and associated with multiple databases. Putative variants were confirmed by Sanger sequencing. The identified variant was classified according to the American College of Medical Genetics (ACMG) criteria. RESULTS:The proband was a 27-year-old Chinese male who presented with short-trunk short stature and joint pain. His radiographs showed platyspondyly with posterior humping, narrow hip-joint surfaces, and pelvic osteosclerosis. A pedigree analysis of 5 generations with 6 affected males revealed an X-linked recessive mode of inheritance. Affected males were diagnosed as SEDT according to the clinical and radiological features. Next-generation sequencing identified a novel variant of c.216_217del in the exon 4 of TRAPPC2 gene in the proband and other affected males. This variant resulted in the shift of reading frame and early termination of protein translation (p.S73Gfs*15). The mother and maternal female relatives of the proband were heterozygous carriers of the same variant, while no variations were detected in this gene of his father and other unaffected males. Based on the ACMG criteria, the novel c.216_217del variant of the TRAPPC2 gene was the pathogenic variant of this SEDT family. CONCLUSION:In this study we identified the novel pathogenic variant of of c.216_217del in the gene of TRAPPC2 in this five-generation Chinese SEDT family. Our findings expand the clinical and molecular spectrum of SEDT and helps the genetic diagnosis of SEDT patients.

Dataset Information

GUCA1A mutation causes maculopathy in a five-generation family with a wide spectrum of severity.

Publications

GUCA1A mutation causes maculopathy in a five-generation family with a wide spectrum of severity.

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