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Abstract

Hearing loss is the most frequent sensory defect in humans. Dozens of genes may be responsible for the early onset forms of isolated deafness and several hundreds of syndromes with hearing loss have been described. Both the difficulties encountered by linkage analysis in families affected by isolated deafness and the paucity of data concerning the molecular components specifically involved in the peripheral auditory process, have long hampered the identification of genes responsible for hereditary hearing loss. Rapid progress is now being made in both fields. This should allow completion of major pieces of the jigsaw for understanding the development and function of the ear.

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Most cited references 77

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Homozygosity mapping: a way to map human recessive traits with the DNA of inbred children.

E Lander, D Botstein (1987)

An efficient strategy for mapping human genes that cause recessive traits has been devised that uses mapped restriction fragment length polymorphisms (RFLPs) and the DNA of affected children from consanguineous marriages. The method involves detection of the disease locus by virtue of the fact that the adjacent region will preferentially be homozygous by descent in such inbred children. A single affected child of a first-cousin marriage is shown to contain the same total information about linkage as a nuclear family with three affected children. Calculations show that it should be practical to map a recessive disease gene by studying DNA from fewer than a dozen unrelated, affected inbred children, given a complete RFLP linkage map. The method should make it possible to map many recessive diseases for which it is impractical or impossible to collect adequate numbers of families with multiple affected offspring.

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microphthalmia, a critical factor in melanocyte development, defines a discrete transcription factor family.

M. Hodgkinson, H Arnheiter, Jessica N Copeland … (1994)

The microphthalmia (mi) gene appears essential for pigment cell development and/or survival, based on its mutation in mi mice. It has also been linked to the human disorder Waardenburg Syndrome. The mi gene was recently cloned and predicts a basic/helix-loop-helix/leucine zipper (b-HLH-ZIP) factor with tissue-restricted expression. Here, we show that Mi protein binds DNA as a homo- or heterodimer with TFEB, TFE3, or TFEC, together constituting a new MiT family. Mi can also activate transcription through recognition of the M box, a highly conserved pigmentation gene promoter element, and may thereby determine tissue-specific expression of pigmentation enzymes. Six mi mutations shown recently to cluster in the b-HLH-ZIP region produce surprising and instructive effects on DNA recognition and oligomerization. An alternatively spliced exon located outside of the b-HLH-ZIP region is shown to significantly modulate DNA recognition by the basic domain. These findings suggest that Mi's critical roles in melanocyte survival and pigmentation are mediated by MiT family interactions and transcriptional activities.

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Skeletal overgrowth and deafness in mice lacking fibroblast growth factor receptor 3.

Christopher Colvin, Alastair G. McEwen, B Bohne … (1996)

Fibroblast growth factor receptor 3 (Fgfr3) is a tyrosine kinase receptor expressed in developing bone, cochlea, brain and spinal cord. Achondroplasia, the most common genetic form of dwarfism, is caused by mutations in FGFR3. Here we show that mice homozygous for a targeted disruption of Fgfr3 exhibit skeletal and inner ear defects. Skeletal defects include kyphosis, scoliosis, crooked tails and curvature and overgrowth of long bones and vertebrae. Contrasts between the skeletal phenotype and achondroplasia suggest that activation of FGFR3 causes achondroplasia. Inner ear defects include failure of pillar cell differentiation and tunnel of Corti formation and result in profound deafness. Our results demonstrate that Fgfr3 is essential for normal endochondral ossification and inner ear development.

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PubMed ID:: 8944017

DOI:: 10.1038/ng1296-385

ScienceOpen disciplines: Chemistry

Keywords: Chromosome Mapping,Deafness,genetics,Ear,physiology,Hearing,Humans,Syndrome

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ScienceOpen disciplines: Chemistry

Keywords: Chromosome Mapping, Deafness, genetics, Ear, physiology, Hearing, Humans, Syndrome

Genes responsible for human hereditary deafness: symphony of a thousand.

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Abstract

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Genes & Diseases

Most cited references 77

Homozygosity mapping: a way to map human recessive traits with the DNA of inbred children.

microphthalmia, a critical factor in melanocyte development, defines a discrete transcription factor family.

Skeletal overgrowth and deafness in mice lacking fibroblast growth factor receptor 3.

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