Spectrum of MYO7A Mutations in an Indigenous South African Population Further Elucidates the Nonsyndromic Autosomal Recessive Phenotype of DFNB2 to Include Both Homozygous and Compound Heterozygous Mutations.

Rosemary Ida Kabahuma,Xue Zhong Liu,Wolf-Dieter Schubert,Christiaan Labuschagne,Denise Yan,Michael Sean Pepper,Susan Halloran Blanton

doi:10.3390/genes12020274

Abstract

MYO7A gene encodes unconventional myosin VIIA, which, when mutated, causes a phenotypic spectrum ranging from recessive hearing loss DFNB2 to deaf-blindness, Usher Type 1B (USH1B). MYO7A mutations are reported in nine DFNB2 families to date, none from sub-Saharan Africa.In DNA, from a cohort of 94 individuals representing 92 families from the Limpopo province of South Africa, eight MYO7A variations were detected among 10 individuals. Family studies identified homozygous and compound heterozygous mutations in 17 individuals out of 32 available family members. Four mutations were novel, p.Gly329Asp, p.Arg373His, p.Tyr1780Ser, and p.Pro2126Leufs*5. Two variations, p.Ser617Pro and p.Thr381Met, previously listed as of uncertain significance (ClinVar), were confirmed to be pathogenic. The identified mutations are predicted to interfere with the conformational properties of myosin VIIA through interruption or abrogation of multiple interactions between the mutant and neighbouring residues. Specifically, p.Pro2126Leufs*5, is predicted to abolish the critical site for the interactions between the tail and the motor domain essential for the autoregulation, leaving a non-functional, unregulated protein that causes hearing loss. We have identified MYO7A as a possible key deafness gene among indigenous sub-Saharan Africans. The spectrum of MYO7A mutations in this South African population points to DFNB2 as a specific entity that may occur in a homozygous or in a compound heterozygous state.

Highlights

MYO7A encodes an unconventional myosin, myosin VIIA, which, when mutated, causes a phenotypic spectrum ranging from recessive nonsyndromic hearing loss (DFNB2) to syndromic deaf-blindness, Usher Type 1B (USH1B)
Elucidation of the three distinct forms of Usher Syndrome Type 1 demonstrated that USH1B, USH1C, and USH1D are distinct genetic disorders caused by mutations in three different genes, MYO7A, CHD23, and USH1C, respectively [1,2,3,4,5]
Both harmonin and myosin VIIA localize along the length of stereocilia, but the three Usher proteins are localized at the upper-tip link density (UTLD), where they associate with the tip link and regulate the function of mechanoelectrical transduction (MET) [22,23,24,25]

Summary

Introduction

MYO7A encodes an unconventional myosin, myosin VIIA, which, when mutated, causes a phenotypic spectrum ranging from recessive nonsyndromic hearing loss (DFNB2) to syndromic deaf-blindness, Usher Type 1B (USH1B). In the assembly (Figure 1), the cytoplasmic tail of CDH23 binds to the PDZ domain scaffolding protein harmonin (USH1C), which in turn forms a tripartite complex with the ankyrin-repeat SANS adaptor (USH1G), and which in turn binds to the tail domain of myosin VIIA [17,26]. The cooperation of these three proteins is essential because the earliest connections between the growing stereocilia are critical for shaping the hair bundle as a coherent unit. Failure of this interaction lea3dosf 26 to disorganized stereocilia and to hearing loss

Methods

Results

Discussion

Conclusion