Severe deafness or hearing impairment is the most prevalent inherited sensory disorder, affecting about 1 in 1,000 children. Most deafness results from peripheral auditory defects that occur as a consequence of either conductive (outer or middle ear) or sensorineuronal (cochlea) abnormalities. Although a number of mutant genes have been identified that are responsible for syndromic (multiple phenotypic disease) deafness such as Waardenburg syndrome and Usher 1B syndrome, little is known about the genetic basis of non-syndromic (single phenotypic disease) deafness. Here we study a pedigree containing cases of autosomal dominant deafness and have identified a mutation in the gene encoding the gap-junction protein connexin 26 (Cx26) that segregates with the profound deafness in the family. Cx26 mutations resulting in premature stop codons were also found in three autosomal recessive non-syndromic sensorineuronal deafness pedigrees, genetically linked to chromosome 13q11-12 (DFNB1), where the Cx26 gene is localized. Immunohistochemical staining of human cochlear cells for Cx26 demonstrated high levels of expression. To our knowledge, this is the first non-syndromic sensorineural autosomal deafness susceptibility gene to be identified, which implicates Cx26 as an important component of the human cochlea.

Connexin 26 mutations in hereditary non-syndromic sensorineural deafness

Pendred syndrome is a recessively inherited disorder with the hallmark features of congenital deafness and thyroid goitre. By some estimates, the disorder may account for upwards of 10% of hereditary deafness. Previous genetic linkage studies localized the gene to a broad interval on human chromosome 7q22-31.1. Using a positional cloning strategy, we have identified the gene (PDS) mutated in Pendred syndrome and found three apparently deleterious mutations, each segregating with the disease in the respective families in which they occur. PDS produces a transcript of approximately 5 kb that was found to be expressed at significant levels only in the thyroid. The predicted protein, pendrin, is closely related to a number of known sulphate transporters. These studies provide compelling evidence that defects in pendrin cause Pendred syndrome thereby launching a new area of investigation into thyroid physiology, the pathogenesis of congenital deafness and the role of altered sulphate transport in human disease.

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Pendred syndrome is caused by mutations in a putative sulphate transporter gene (PDS)

Molecular Motors in Neurons: Transport Mechanisms and Roles in Brain Function, Development, and Disease

Myosins: a diverse superfamily.

Assessment of hearing in 80 inbred strains of mice by ABR threshold analyses.

USHER syndrome represents the association of a hearing impairment with retinitis pigmentosa1 and is the most frequent cause of deaf–blindness in humans. It is inherited as an autosomal recessive trait which is clinically and genetically heterogeneous2,3. Some patients show abnormal organization of microtubules in the axoneme of their photoreceptors cells (connecting cilium)4–6, nasal ciliar cells7 and sperm cells5, as well as widespread degeneration of the organ of Corti8. Usher syndrome type 1 (USH1) is characterized by a profound congenital sensorineural hearing loss, constant vestibular dysfunction and prepubertal onset of retinitis pigmentosa. Of three different genes responsible for USH19–11,USH1B maps to 11q13.5 (ref. 10) and accounts for about 75% of USH1 patients2,3. The mouse deafness shaker-1 (shl) mutation has been localized to the homologous murine region12,13. Taking into account the cytoskeletal abnormalities in USH patients, the identification of a gene encoding an unconventional myosin as a candidate for shaker-1(ref. 14) led us to consider the human homo-logue as a good candidate for the gene that is defective in USH1B. Here we present evidence that a gene encoding myosin VIIA is responsible for USH1B. Two different premature stop codons, a six-base-pair deletion and two different missense mutations were detected in five unrelated families. In one of these families, the mutations were identified in both alleles. These mutations, which are located at the amino-terminal end of the motor domain of the protein, are likely to result in the absence of a functional protein. Thus USH IB appears as a primary cytoskeletal protein defect. These results implicate the genes encoding other unconventional myosins and their interacting proteins as candidates for other genetic forms of Usher syndrome.

Dominique Larget-Piet

Papers

Defective myosin VIIA gene responsible for Usher syndrome type 1B