MYO15A (DFNB3) mutations in Turkish hearing loss families and functional modeling of a novel motor domain mutation

Abstract

Myosin XVA is an unconventional myosin which has been implicated in autosomal recessive nonsyndromic hearing impairment (ARNSHI) in humans. In Myo15A mouse models, vestibular dysfunction accompanies the autosomal recessive hearing loss. Genomewide homozygosity mapping and subsequent fine mapping in two Turkish families with ARNSHI revealed significant linkage to a critical interval harboring a known deafness gene MYO15A on chromosome 17p13.1-17q11.2. Subsequent sequencing of the MYO15A gene led to the identification of a novel missense mutation, c.5492G-->T (p.Gly1831Val) and a novel splice site mutation, c.8968-1G-->C. These mutations were not detected in additional 64 unrelated ARNSHI index patients and in 230 Turkish control chromosomes. Gly1831 is a conserved residue located in the motor domains of the different classes of myosins of different species. Molecular modeling of the motor head domain of the human myosin XVa protein suggests that the Gly1831Val mutation inhibits the powerstroke by reducing backbone flexibility and weakening the hydrophobic interactions necessary for signal transmission to the converter domain.

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

“…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. 101 RDX gene RDX gene (MIM 179410, GeneID 5962) has been mapped on chromosome 11q23, encoding a cytoskeletal protein named radixin, which possibly functions as linking molecule between actin and plasma membrane.…”

Identification and Clinical Implications of a Novel MYO15A Variant in a Consanguineous Iranian Family by Targeted Exome Sequencing

“…Genetic causes of HL have been studied in Iranian populations Koohiyan et al, 2018;Azadegan-Dehkordi et al, 2019a]. Approximately 5.7% of Iranian patients affected by ARNSHL are due to MYO15A mutations while the frequency of the MYO15A mutations causing ARNSHL has been reported as 9.9% in Turkey [Kalay et al, 2007]. Mutations of MYO15A are perhaps the third most common cause of HL and have been identified in sequence encoding all of the domains and motifs of this protein [Santos-Cortez et al, 2016].…”

“…This particle includes MyTH4 (myosin tail homologue 4), FERM (band 4.1erin/radixin/moesin) and SH3 (scr-homology-3) domains and ITLL (class PDZ ligand) at the C terminus. Several studies have linked mutations in MYO15A to HL, while most of the related mutations have been identified by linkage analysis in consanguineous families from specific countries such as Pakistan, Turkey and Iran [Kalay et al, 2007;Bashir et al, 2012]. Until now, more than 120 mutations in MYO15A have been reported, 15 of which are from the Iran.…”

Microdeletion on 17p11.2 in a Smith-Magenis syndrome patient with mental retardation and congenital heart defect: first report from China

“…Mutations or deletions of ALDH3A2, which encode an enzyme that catalyzes the oxidation of fatty aldehyde to fatty acid, have been shown to cause an autosomal recessive disorder Sjogren-Larsson syndrome (Engelstad et al, 2011). MYO15A has been identified to be responsible for deafness (Kalay et al, 2007). However, due to the lack of molecular data and small sample size in previous studies, the precise gene(s) responsible for CHD in SMS is still unclear.…”