Mutational Spectrum ofMYO15Aand the Molecular Mechanisms of DFNB3 Human Deafness

Abstract

Deafness in humans is a common neurosensory disorder and is genetically heterogeneous. Across diverse ethnic groups, mutations of MYO15A at the DFNB3 locus appear to be the third or fourth most common cause of autosomal recessive, nonsyndromic deafness. In 49 of the 67 exons of MYO15A, there are currently 192 recessive mutations identified, including 14 novel mutations reported here. These mutations are distributed uniformly across MYO15A with one enigmatic exception; the alternatively spliced giant exon 2, encoding 1,233 residues, has 17 truncating mutations but no convincing deafness-causing missense mutations. MYO15A encodes three distinct isoform classes, one of which is 395 kDa (3,530 residues), the largest member of the myosin superfamily of molecular motors. Studies of Myo15 mouse models that recapitulate DFNB3 revealed two different pathogenic mechanisms of hearing loss. In the inner ear, myosin 15 is necessary both for the development and the long-term maintenance of stereocilia, mechanosensory sound-transducing organelles that extend from the apical surface of hair cells. The goal of this Mutation Update is to provide a comprehensive review of mutations and functions of MYO15A.

A homozygous missense variant in CACNB4 encoding the auxiliary calcium channel beta4 subunit causes a severe neurodevelopmental disorder and impairs channel and non-channel functions

“…(Arg297Cys) in DHX38 (MIM: 605584) in which two other amino acid substitutions have been reported in individuals with autosomal recessively inherited early-onset retinitis pigmentosa (MIM: 268000) [52,53] and c.5083C>A/p. (Pro1695Thr) in MYO15A (MIM: 602666) in which biallelic mutations cause autosomal-recessive, nonsyndromic deafness (DFNB3, MIM: 600316) [54,55]. The MYO15A change c.5083C>A is no known disease-associated allele.…”

Analysis of mutation spectrum of common deafness-causing genes in Hakka newborns in southern China by semiconductor sequencing

“…[ 10 – 12 ] At present, previous genetic screening studies have shown that a few genes mutations are known to cause hereditary hearing loss or deafness, such as GJB2 (gap junction beta-2 protein; OMIM: 121011), GJB3 (gap junction beta-2 protein; OMIM: 603324), SLC26A4 (solute carrier family 26 member 4; OMIM: 605646), and the mitochondrial gene MT-RNR1 (mitochondrially encoded 12S RNA; OMIM: 561000). [ 9 , 13 – 24 ] Knowledge of the gene mutation can help to identify hearing impairment at birth, and the educational programs for auditory stimulation and sufficient language exposure in early childhood can begin immediately. Furthermore, it can also provide warning to avoid taking certain types of aminoglycosides antibiotics, such as streptomycin, gentamicin, and tobramycin, which are known to cause deafness in children carrying certain mitochondrial gene mutations.…”

Association of a novel missense mutation in MYO15A with nonsyndromic hearing loss: a case report

“…Myosin XVA is an unconventional myosin encoded by the human MYO15A gene and consists of 3530 amino acids. It is expressed at the tips of hair cell stereocilia in the inner cochlear region [7][8][9]. Three evolutionally conserved regions (head, neck, and tail) are present in this protein.…”