Mutation Profile of All 49 Exons of the Human Myosin VIIA Gene, and Haplotype Analysis, in Usher 1B Families from Diverse Origins

Abstract

Usher syndrome types I (USH1A-USH1E) are a group of autosomal recessive diseases characterized by profound congenital hearing loss, vestibular areflexia, and progressive visual loss due to retinitis pigmentosa. The human myosin VIIA gene, located on 11q14, has been shown to be responsible for Usher syndrome type 1B (USH1B). Haplotypes were constructed in 28 USH1 families by use of the following polymorphic markers spanning the USH1B locus: D11S787, D11S527, D11S1789, D11S906, D11S4186, and OMP. Affected individuals and members of their families from 12 different ethnic origins were screened for the presence of mutations in all 49 exons of the myosin VIIA gene. In 15 families myosin VIIA mutations were detected, verifying their classification as USH1B. All these mutations are novel, including three missense mutations, one premature stop codon, two splicing mutations, one frameshift, and one deletion of >2 kb comprising exons 47 and 48, a part of exon 49, and the introns between them. Three mutations were shared by more than one family, consistent with haplotype similarities. Altogether, 16 USH1B haplotypes were observed in the 15 families; most haplotypes were population specific. Several exonic and intronic polymorphisms were also detected. None of the 20 known USH1B mutations reported so far in other world populations were identified in our families.

Myosin VIIa Participates in Opsin Transport through The Photoreceptor Cilium

“…These may also be effective null mutations, but, in all cases except two, patients are not homozygous null (Weil et al, 1995;Weston et al, 1996;Adato et al, 1997;Levy et al, 1997;Liu et al, 1997b). The only possible exceptions have been found in (1) two siblings of an isolated family who appeared to be homozygous for a single base substitution, resulting in a Y333stop mutation (Weston et al, 1996); and (2) three siblings of an isolated family who appeared to be homozygous for a single base substitution, resulting in a C638stop mutation (Cuevas et al, 1998).…”

Deafness Genes and Their Diagnostic Applications

“…A loss of function of MYO6 most likely causes DFNB37, while a dominant-negative or gain-of-function mechanism probably underlies the DFNA22 deafness phenotype [Ahmed et al, 2003]. Also the MYO7A gene can lead to a wide range of deafness phenotypes, including Usher syndrome type IB [Adato et al, 1997;Levy et al, 1997;Liu et al, 1997a;Weil et al, 1995]. Usher syndrome is an autosomal recessive disorder characterized by sensorineural HI and retinitis pigmentosa.…”

Identification of novel USH2A mutations: implications for the structure of USH2A protein

“…These are MYO7A and USH2A in Usher type I and Usher type II, respectively. So far, 46 mutations likely to be disease-causing have been identified in MYO7A and no single mutation appears to predominate, [15][16][17][18][19][20] except for a probable founder mutation (C31X) which accounted for 50% of the mutations in the Danish Usher type I patients. 20 In Usher type IIa patients, however, the 2299delG mutation, reported in patients from Scandinavia (Denmark, Norway and Sweden), Northern and Southern Europe, North America, UK and China dominate the mutational spectrum (frequency ranging from 0.15 to 0.44).…”