Mutational spectrum ofMYO15A: the large N-terminal extension of myosin XVA is required for hearing

Abstract

Human MYO15A is located on chromosome 17p11.2, has 66 exons and encodes unconventional myosin XVA. Recessive mutations of MYO15A are associated with profound, nonsyndromic hearing loss DFNB3 in humans, and deafness and circling behavior in shaker 2 mice. In the inner ear, this motor protein is necessary for the development of hair cell stereocilia, which are actin-filled projections on the apical surface and the site of mechanotransduction of sound. The longest isoform of myosin XVA has 3,530 amino acid residues. Two isoform classes of MYO15A are distinguished by the presence or absence of 1,203 residues preceding the motor domain encoded by alternatively-spliced exon 2. It is not known whether this large N-terminal extension of myosin XVA is functionally necessary for hearing. We ascertained approximately 600 consanguineous families segregating hereditary hearing loss as a recessive trait and found evidence of linkage of markers at the DFNB3 locus to hearing loss in 38 of these families ascertained in Pakistan (n=30), India (n=6), and Turkey (n=2). In this study, we describe 16 novel recessive mutations of MYO15A associated with severe to profound hearing loss segregating in 20 of these DFNB3-linked families. Importantly, two homozygous mutant alleles-c.3313G>T (p.E1105X) and c.3334delG (p.G1112fsX1124) of MYO15A-located in exon 2 are associated with severe to profound hearing loss segregating in two families. These data demonstrate that isoform 1, containing the large N-terminal extension, is also necessary for normal hearing.

Unexpected genetic heterogeneity in a large consanguineous Brazilian pedigree presenting deafness

“…1 -4 Among all DFNB loci, the most prevalent one is DFNB1 (GJB2 and GJB6 genes, 5 -6 MIM 121011 and 604418) that accounts for up to 50% of recessive cases. Other loci with a significant number of different families associated are DFNB4 (SLC26A4 gene, 7 MIM 605646), DFNB9 (OTOF gene, 8 MIM 603681), DFNB12 (CDH23 gene, 9 MIM 605516), DFNB7/11 (TMC1 gene, 10 MIM 606706), followed by DFNB8/10 (TMPRSS3 gene, 11 MIM 605511) and DFNB3 (MYO15A gene, 12 MIM 602666).…”

Genetic causes of nonsyndromic hearing loss in Iran in comparison with other populations

“…Mutations in this large gene can cause autosomal recessive HL (DFNB3) and account for 5% of ARNSHL in Pakistan. 7,95,98,99 Two MYO15A mutations have also been reported in 66 ARNSHI Turkish families. 100 More recently, two homozygous missense mutations were exemplified in two consanguineous Iranian families; c.6371G4A and c.6555C4T lead to p.R2124Q and p.P2073S amino-acid substitutions.…”

Genetics of Nonsyndromic Recessively Inherited Moderate to Severe and Progressive Deafness in Humans

“…The mutations in alternatively spliced exon 2 affect the class 1 isoform of MYO15A which has a long N-terminal extension. The presence of residual hearing in affected individuals who have mutations in exon 2 of MYO15A is probably due to the availability of normally functioning short isoform of MYO15A which remains unaffected by the mutations in exon 2 (Nal et al, 2007).…”