Novel missense mutations in MYO7A underlying postlingual high- or low-frequency non-syndromic hearing impairment in two large families from China

Abstract

The myosin VIIA (MYO7A) gene encodes a protein classified as an unconventional myosin. Mutations within MYO7A can lead to both syndromic and non-syndromic hearing impairment in humans. Among different mutations reported in MYO7A, only five led to non-syndromic sensorineural deafness autosomal dominant type 11 (DFNA11). Here, we present the clinical, genetic and molecular characteristics of two large Chinese DFNA11 families with either high-or low-frequency hearing loss. Affected individuals of family DX-J033 have a sloping audiogram at young ages with high frequency are most affected. With increasing age, all test frequencies are affected. Affected members of family HB-S037 present with an ascending audiogram affecting low frequencies at young ages, and then all frequencies are involved with increasing age. Genome-wide linkage analysis mapped the disease loci within the DFNA11 interval in both families. DNA sequencing of MYO7A revealed two novel nucleotide variations, c.652G4A (p.D218N) and c.2011G4A (p.G671S), in the two families. It is for the first time that the mutations identified in MYO7A in the present study are being implicated in DFNA11 in a Chinese population. For the first time, we tested electrocochleography (ECochG) in a DFNA11 family with low-frequency hearing loss. We speculate that the low-frequency sensorineural hearing loss in this DFNA11 family was not associated with endolymphatic hydrops.

Identification and Functional Study of a New Missense Mutation in the Motor Head Domain of Myosin VIIA in a Family with Autosomal Dominant Hearing Impairment (DFNA11)

“…Until now, only seven mutations in the MYO7A were known to segregate with DFNA11. Five of the seven mutations were located in the motor domain of the myosin VIIA gene, including p.G722R, p.N458I, p.A230V, p.D218N and p.G671S [10], [11], [12], [13]. In the present study, we identified an eighth mutation in a family in which progressive non-syndromic autosomal dominant hearing loss segregates with the DFNA11 locus.…”

“…Until now, only seven mutations in the myosin VIIA gene have been identified as being correlated with DFNA11: p.A886_K888del in the coiled coil region [5], [9], p.G722R, p.N458I, p.A230V, p.D218N and p.G671S in the motor domain [10], [11], [12], [13] and p.R853C in the IQ motif [14].…”

Comprehensive Genetic Analysis of Japanese Autosomal Dominant Sensorineural Hearing Loss Patients

“…Some mutations ( WFS1 : c.2590G>A (p.E864K), MYO7A : c.652G>A (p.D218N) and ACTG1 : c.353A>T (p.K118M)) were previously reported in different populations[25, 29–31]. Therefore, they may be hot spot mutations rather than founder mutations.…”

WFS1 and GJB2 mutations in patients with bilateral low‐frequency sensorineural hearing loss

“…Low‐frequency sensorineural hearing loss (LFSNHL) shows a characteristic configuration of audiogram, and is much less common than high‐frequency hearing loss and flat‐type hearing loss in nonsyndromic sensorineural hearing loss (SNHL) . Four genes— DIAPH1 , MYO7A , WFS1 , and CCD50 —are known to be responsible for nonsyndromic hereditary LFSNHL in autosomal dominant nonsyndromic deafness 1 (DFNA1), DFNA11, DFNA6/14/38, and DFNA44, respectively . DFNA54 is another form of nonsyndromic hereditary LFSNHL; however, the responsible gene(s) is yet to be identified .…”

“…[3][4][5][6] Four genes-DIAPH1, MYO7A, WFS1, and CCD50-are known to be responsible for nonsyndromic hereditary LFSNHL in autosomal dominant nonsyndromic deafness 1 (DFNA1), DFNA11, DFNA6/14/ 38, and DFNA44, respectively. 3,4,[7][8][9][10] DFNA54 is another form of nonsyndromic hereditary LFSNHL; however, the responsible gene(s) is yet to be identified. 5 Among these genes, WFS1 accounts for the largest number of familial cases.…”