The autosomal recessive isolated deafness, DFNB2, and the Usher 1B syndrome are allelic defects of the myosin-VIIA gene

Abstract

Hereditary non-syndromic profound deafness affects about 1 in 2000 children prior to language acquisition. In 80% of the cases, the mode of transmission is autosomal recessive. The number of genes involved in these recessive forms of isolated deafness (DFNB genes) has been estimated to between 30 and 100. So far, ten DFNB genes have been mapped to human chromosomes, one of which has been isolated. By linkage analysis of a single family whose members were affected with profound deafness, some of them presenting with vestibular dysfunction, DFNB2 has been mapped to chromosome 11q13 (ref. 3). The gene responsible for a form of Usher syndrome type I, USH1B, has been assigned to the same chromosomal region. Usher syndrome associates profound congenital deafness and vestibular dysfunction with retinitis pigmentosa. In the homologous murine region are located the shaker-1 mutations responsible for deafness and vestibular dysfunction. It has been demonstrated that the murine shaker-1 and human USH1B phenotypes result from mutations in the gene encoding myosin-VIIA. Based on mapping data as well as on the similarities between the phenotypes of DFNB2-affected patients and shaker-1 mouse mutants, we have proposed that a defective myosin-VIIA may also be responsible for DFNB2 (ref. 1). Sequence analysis of each of the coding exons of the myosin-VIIA gene (MYO7A) was thus undertaken in the DFNB2-affected family. In the last nucleotide of exon 15, a G to A transition was detected, a type of mutation that is known to decrease the efficiency of splicing. Accordingly, this result shows that different mutations in MYO7A result in either an isolated or a syndromic form of deafness.

Progressive Hearing Loss and Increased Susceptibility to Noise-Induced Hearing Loss in Mice Carrying a Cdh23 but not a Myo7a Mutation

“…Patients with USH1 are congenitally deaf, have vestibular dysfunction, and develop retinitis pigmentosa (Smith et al 1994). Both genes have also been shown to underlie nonsyndromic forms of deafness (Liu et al 1997a,b;Weil et al 1997;Bork et al 2001). Recently, Myo7a and Cdh23 were both shown to bind to harmonin suggesting that these molecules form a functional complex within the stereocilia (Boeda et al 2002).…”

A novel locus for Usher syndrome type II, USH2B, maps to chromosome 3 at p23–24.2

“…Therefore, the possibility that a single gene underlies both USH2B and DFNB6 should be considered. Such a situation has already been shown for USH1B and DFNB2, 8,15,16 and may also apply to USH1C and DFNB18 4,18 or USH3 and DFNB15, 14,19 which colocalise. In the frame of this hypothesis, a more deleterious mutation for USH2B than for DFNB6 would be expected.…”

“…Indeed, it has been shown that MYO7A, the gene encoding myosin VIIA, is responsible for both USH1B 15 and an isolated form of recessive deafness, DFNB2. 8,16 During this exclusion mapping, linkage was observed with marker AFM198yf2 (locus D3S1289) which is located within the candidate interval defined for DFNB6 at 3p24. 17 Eight microsatellite markers were used to map the USH2 locus involved in Usher syndrome in family Us.…”

“…Only the gene responsible for USH1B has been identified. 8 The prevalence of Usher type II syndrome in the general population in Europe and the USA has been estimated at 1/100 000. Evidence for genetic heterogeneity of this syndrome was reported several years ago, 9 but only one locus, USH2A, has been identified to date.…”

A second Middle Eastern kindred with autosomal recessive non-syndromic hearing loss segregates DFNB9

“…Thus far, 16 autosomal recessive hearing loss genes (DFNB) have been localized, of which two have been isolated: the unconventional myosin VIIa gene for DFNB2 1,2 and Connexin 26 3 for DFNB1.…”