Identification and Clinical Implications of Novel MYO15A Mutations in a Non-consanguineous Korean Family by Targeted Exome Sequencing

• Published in: Molecules and cells 2015, 38(9), , pp.781-788
• Main Authors: Chang, M.Y., Seoul National University Hospital, Seoul national University College of Medicine, Seoul, Republic of Korea, Kim, A.R., Seoul National University Hospital, Seoul national University College of Medicine, Seoul, Republic of Korea, Kim, N.K.D., Samsung Medical Center, Seoul, Republic of Korea, Lee, C., Samsung Medical Center, Seoul, Republic of Korea, Lee, K.Y., Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea, Jeon, W.S., Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea, Oh, S.H., Seoul National University Hospital, Seoul national University College of Medicine, Seoul, Republic of Korea, Park, W.Y., Samsung Medical Center, Seoul, Republic of Korea, Kim, D., Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea, Choi, B.Y., Seoul National University Bundang Hospital, Seongnam, Republic of Korea, Koo, J.W., Seoul National University Bundang Hospital, Seongnam, Republic of Korea
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Base Sequence; Binding Sites; Cochlear Implantation; cochlear implantation,MYO15A,nonsyndromic sensorineural hearing loss(NSHL); Deafness - genetics; Deafness - surgery; DNA Mutational Analysis; Exome; Female; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Infant; Male; Models, Molecular; Molecular Sequence Data; MUTACION; MUTATION; Mutation, Missense; Myosins - chemistry; Myosins - genetics; Pedigree; Republic of Korea; Sequence Analysis, RNA; 생물학
• ISSN: 1016-8478; 0219-1032
• DOI: 10.14348/molcells.2015.0078

Mutations of MYO15A are generally known to cause severe to profound hearing loss throughout all frequencies. Here, we found two novel MYO15A mutations, c.3871CT (p.L1291F) and c.5835TG (p.Y1945X) in an affected individual carrying congenital profound sensorineural hearing loss (SNHL) through targeted resequencing of 134 known deafness genes. The variant, p.L1291F and p.Y1945X, resided in the myosin motor and IQ2 domains, respectively. The p.L1291F variant was predicted to affect the structure of the actin-binding site from three-dimensional protein modeling, thereby interfering with the correct interaction between actin and myosin. From the literature analysis, mutations in the N-terminal domain were more frequently associated with residual hearing at low frequencies than mutations in the other regions of this gene. Therefore we suggest a hypothetical genotype-phenotype correlation whereby MYO15A mutations that affect domains other than the N-terminal domain, lead to profound SNHL throughout all frequencies and mutations that affect the N-terminal domain, result in residual hearing at low frequencies. This genotype-phenotype correlation suggests that preservation of residual hearing during auditory rehabilitation like cochlear implantation should be intended for those who carry mutations in the N-terminal domain and that individuals with mutations elsewhere in MYO15A require early cochlear implantation to timely initiate speech development.