Novel and Recurrent MYO7A Mutations in Usher Syndrome Type 1 and Type 2

Abstract

Usher syndrome (USH) is a group of disorders manifested as retinitis pigmentosa and bilateral sensorineural hearing loss, with or without vestibular dysfunction. Here, we recruited three Chinese families affected with autosomal recessive USH for detailed clinical evaluations and for mutation screening in the genes associated with inherited retinal diseases. Using targeted next-generation sequencing (NGS) approach, three new alleles and one known mutation in MYO7A gene were identified in the three families. In two families with USH type 1, novel homozygous frameshift variant p.Pro194Hisfs*13 and recurrent missense variant p.Thr165Met were demonstrated as the causative mutations respectively. Crystal structural analysis denoted that p.Thr165Met would very likely change the tertiary structure of the protein encoded by MYO7A. In another family affected with USH type 2, novel biallelic mutations in MYO7A, c.[1343+1G>A];[2837T>G] or p.[?];[Met946Arg], were identified with clinical significance. Because MYO7A, to our knowledge, has rarely been correlated with USH type 2, our findings therefore reveal distinguished clinical phenotypes associated with MYO7A. We also conclude that targeted NGS is an effective approach for genetic diagnosis for USH, which can further provide better understanding of genotype-phenotype relationship of the disease.

Targeted next generation sequencing for molecular diagnosis of Usher syndrome

“…Yoshimura et al [ 38 ] has also applied a massively parallel DNA sequencing methodology, but only for USH1 patients. Recently, Rong W et al [ 39 ] used the NGS approach to identify three new alleles and one known mutation in MYO7A in three Chinese families.…”

Exome Sequencing RevealsAGBL5as Novel Candidate Gene and Additional Variants for Retinitis Pigmentosa in Five Turkish Families

“…5 It is divided into three subtypes (USH1, USH2, and USH3) all including retinal degeneration but mainly differing in severity and progression of neurosensory deafness as well as variable impairment of the vestibular system. 6 Both non-syndromic RP and Usher syndrome have been shown to be highly heterogeneous. At present, mutations in >60 genes have been identified as causative for non-syndromic RP and twelve genes are known for Usher syndrome.…”

A Founder Mutation inMYO7AUnderlies a Significant Proportion of Usher Syndrome in Indigenous South Africans: Implications for the African Diaspora

“…This is not the first report of MYO7A mutations causing type 2 USH, 14 but the observation is rare. The milder phenotype diagnosed could be due to the fact that the mutation affects the C-terminal FERM domain, and less than 4% of the protein is predicted to be truncated.…”

“…14,15 The protein MYO7A is an unconventional myosin expressed in multiple epithelial cell types, 16 including the RPE, where it functions in the light-dependent localization of the visual cycle enzyme, RPE65. 17 It is also expressed in the photoreceptor calyceal processes and cilia, and the stereocilia, together with other USH proteins.…”