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Compound heterozygous mutations in SMO associated with anterior segment dysgenesis and morning glory syndrome

Zhang, Jing, Li, Yue, Fan, Yidan, Wu, Dan, Xu, Jianjiang
Gene 2019 v.713 pp. 143973
G-protein coupled receptors, bioinformatics, cataract, cornea, gene frequency, gene therapy, genes, heterozygosity, mice, mutants, mutation, opacity, patients, phenotype, sequence analysis, signal transduction
Eye development in vertebrates is a highly coordinated multistep process while defects in key factors might lead to severe congenital ocular disorders. SMO encodes a G protein-coupled receptor that functions in Hedgehog signal transduction, an essential step during eye development. Here we reported the first identification of compound heterozygous mutations (c.G338A; p.R113Q and c.C1619T; p.A540V) in the SMO gene in a patient with both anterior segment dysgenesis (congenital corneal opacity, cataract) and morning glory syndrome, using trio-based whole exome sequencing. The clinical manifestations of this patient were quite consistent with the phenotypes observed in murine SMO null mutants. In silico bioinformatics analyses showed that the newly identified mutations revealed extremely low allele frequencies in the general populations, and were predicted to affect SMO protein stability and residues physiochemical properties. Further investigations revealed a significant decrease of SMO expression in the patient compared with healthy controls (0.71 ± 0.04 vs. 1.49 ± 0.29, P = 0.0265). Therefore, this study pinpoints, for the first time, the potential key sites in SMO that contribute to the maintenance of healthy ocular development, highlighting potential targets for upcoming gene therapy.