Abstract
BackgroundAchromatopsia (ACHM) is a severe congenital autosomal recessive retinal disorder caused by loss of cone photoreceptors. Here, we aimed to determine the underlying genetic lesions and phenotypic correlations in two Chinese families with ACHM.MethodsMedical history and clinical evaluation were obtained from both families. Targeted exome sequencing (TES) was performed on 201 disease-causing genes of inherited retinal dystrophies to screen for ACHM causative mutations in the two probands.ResultsThe compound heterozygous mutations in CNGA3 (c.1074G > A, p.W358X; c.1706G > A, p.R569H) were identified in the first proband, and a novel homozygous mutation (c.968C > A, p.A323D) was detected in the other pedigree. The proposed topological model of the CNGA3 polypeptide suggested that the missense mutations primarily affected the transmembrane helix 5 and the cGMP-binding domain, respectively. Crystal structure modeling of the cyclic nucleotide-gated cation channel α-3 (CNGA3) protein encoded by the CNGA3 gene revealed an abnormal combined structure generated by R569H.ConclusionsWe firstly used the TES approach to identify genetic alterations in patients with ACHM. We uncovered three mutations in CNGA3, including one novel mutation. Our results not only expand the genotypic spectrum for CNGA3 mutations, but also demonstrate that the TES approach is a valuable tool for molecular diagnosis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-015-0694-7) contains supplementary material, which is available to authorized users.
Highlights
Achromatopsia (ACHM) is a severe congenital autosomal recessive retinal disorder caused by loss of cone photoreceptors
Mutations in CNGA3 are considered the most common cause of ACHM and cone-rod dystrophies (CORDs) in Chinese, in which only cone photoreceptors are usually affected, CNGA3 mutations have been reported in a patient with CORDs and Leber congenital amaurosis (LCA) [8, 9]
We performed Targeted exome sequencing (TES) to screen 201 disease-causing genes of inherited retinal dystrophies in two families with ACHM, and discovered novel disease causative mutations, which broaden the spectrum of ACHM in Chinese
Summary
Achromatopsia (ACHM) is a severe congenital autosomal recessive retinal disorder caused by loss of cone photoreceptors. Achromatopsia (ACHM) is an early-onset and mostly stationary retinal dystrophy characterized by amblyopia (severely reduced visual acuity), pendular nystagmus, To date, five causative genes (CNGA3, CNGB3, GNAT2, PDE6C and PDE6H) have been identified in ACHM patients [1, 3,4,5,6]. These genes encode crucial components of the cone phototransduction cascade. We performed TES to screen 201 disease-causing genes of inherited retinal dystrophies in two families with ACHM, and discovered novel disease causative mutations, which broaden the spectrum of ACHM in Chinese
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