Identification of novel mutations by targeted exome sequencing and the genotype-phenotype assessment of patients with achromatopsia
| Autor: | Fen‑Fen Li, Zi-Bing Jin, Mei‑Qin Zheng, Jie Chen, Xiu-Feng Huang, De‑Kang Gan, Xu‑Dong Yu, Fan Lu |
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| Jazyk: | angličtina |
| Předmět: |
Proband
Adult Male China Heterozygote Achromatopsia DNA Mutational Analysis Molecular Sequence Data Mutation Missense Cyclic Nucleotide-Gated Cation Channels Color Vision Defects Genes Recessive Biology Genotype-phenotype medicine.disease_cause Compound heterozygosity Crystallography X-Ray General Biochemistry Genetics and Molecular Biology Genotype Retinal Dystrophies medicine Missense mutation Humans Exome Amino Acid Sequence Child Exome sequencing Genetic Association Studies Genetics Family Health Medicine(all) Mutation Biochemistry Genetics and Molecular Biology(all) Research Homozygote Computational Biology General Medicine medicine.disease Novel mutations Pedigree Genetic diagnosis Retinal Cone Photoreceptor Cells Female Targeted exome sequencing |
| Zdroj: | Journal of Translational Medicine |
| ISSN: | 1479-5876 |
| DOI: | 10.1186/s12967-015-0694-7 |
| Popis: | Background Achromatopsia (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. Methods Medical 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. Results The 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. Conclusions We 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 material The online version of this article (doi:10.1186/s12967-015-0694-7) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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