Abstract
Leber congenital amaurosis (LCA) is a group of severe congenital retinal diseases. Variants in the guanylate cyclase 2D gene (GUCY2D), which encodes guanylate cyclase 1 (ROS-GC1), are associated with LCA1 and account for 6%–21% of all LCA cases. In this study, one family with LCA1 was recruited from China. A combination of next generation sequencing and Sanger sequencing was used to screen for disease-causing mutations. We found three novel mutations (c.139delC, p.Ala49Profs*36; c.835G>A, p.Asp279Asn and c.2783G>A, p.Gly928Glu) in the GUCY2D gene. Proband III-2 carries mutations c.139delC and c.2783G>A, which are inherited from the heterozygous mutation carriers, II-2 (c.139delC) and II-3 (c.2783G>A) that possess c.139delC and c.2783G>A. Additionally, II-8 carries heterozygous mutation c.835G>A. Sanger sequencing was used to confirm the presence of the three novel mutations in other family members. Mutation c.139delC results in a truncated protein. Mutations c.835G>A and c.2783G>A significantly reduce the catalytic activity of ROS-GC1. Our findings highlight the gene variants range of LCA. Moreover, HPLC-coupled tandem mass spectrometry (HPLC-MS/MS) was used to analyze the concentration of 3',5'-cyclic guanosine monophosphate (cGMP), suggesting that HPLC-MS/MS is an effective alternative method to evaluate the catalytic activity of wild-type and mutant ROS-GC1.
Highlights
Leber congenital amaurosis (LCA), accounts for at least 5% of all inherited retinal dystrophies, and is the earliest and most severe form of all inherited retinal dystrophies [1]
The results showed that II-7 is a c.2783G>A mutation carrier, and II-8 possesses another novel mutation c.835G>A (Fig 1B3)
We found three novel mutations (c.139delC, c.2783G>A and c.835G>A) in the guanylate cyclase 2D (GUCY2D) gene
Summary
Leber congenital amaurosis (LCA), accounts for at least 5% of all inherited retinal dystrophies, and is the earliest and most severe form of all inherited retinal dystrophies [1]. LCA is generally inherited in an autosomal recessive manner [2,3,4] and characterized by genetic and phenotypic heterogeneity. Mutations in 20 genes are associated with LCA [5]. GUCY2D gene mutations cause Leber congenital amaurosis 1 support in the form of salaries for authors [Xiaoming Wei], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of this author are articulated in the ‘author contributions’ section
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