TY - JOUR
T1 - 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
AU - Kabahuma, Rosemary Ida
AU - Schubert, Wolf Dieter
AU - Labuschagne, Christiaan
AU - Yan, Denise
AU - Blanton, Susan Halloran
AU - Pepper, Michael Sean
AU - Liu, Xue Zhong
N1 - Funding Information:
Funding: This study was supported through the Fulbright Senior Research Scholar Award and the University of Pretoria RDP funding to RI Kabahuma; R01 DC05575 and R01 DC012115 from the National Institutes of Health/National Institute on Deafness and Other Communication Disorders to X.Z.L.
Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/2
Y1 - 2021/2
N2 - 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.
AB - 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.
KW - Compound heterozygous
KW - DFNB2
KW - Homozygous
KW - MYO7A gene
KW - Recessive hearing loss
KW - South African
KW - Spectrum of MYO7A mutations
KW - Sub-Saharan Africa
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U2 - 10.3390/genes12020274
DO - 10.3390/genes12020274
M3 - Article
AN - SCOPUS:85101258409
VL - 12
SP - 1
EP - 26
JO - Genes
JF - Genes
SN - 2073-4425
IS - 2
M1 - 274
ER -