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Relevance of connexin deafness (DFNB1) to human evolution.

ABSTRACT: The connexins are the subunits of a family of proteins that form gap junctions, allowing ions and small molecules to move between adjacent cells. At least four connexins are expressed in the ear, and, although there are known mutations at >100 loci that can cause deafness, those involving DFNB1, in the interval 13q11-q12 containing the GJB2 and GJB6 genes coding for connexins 26 and 30, are the most frequent cause of recessive deafness in many populations. We have suggested that the combined effects of relaxed selection and linguistic homogamy can explain the high frequency of connexin deafness and may have doubled its incidence in this country during the past 200 years. In this report, we show by computer simulation that assortative mating, in fact, can accelerate dramatically the genetic response to relaxed selection. Along with the effects of gene drift and consanguinity, assortative mating also may have played a key role in the joint evolution and accelerated fixation of genes for speech after they first appeared in Homo sapiens 100,000-150,000 years ago.

SUBMITTER: Nance WE

PROVIDER: S-EPMC1182073 | biostudies-literature | 2004 Jun

REPOSITORIES: biostudies-literature

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Relevance of connexin deafness (DFNB1) to human evolution.

Nance Walter E WE Kearsey Michael J MJ

American journal of human genetics 20040409 6

The connexins are the subunits of a family of proteins that form gap junctions, allowing ions and small molecules to move between adjacent cells. At least four connexins are expressed in the ear, and, although there are known mutations at >100 loci that can cause deafness, those involving DFNB1, in the interval 13q11-q12 containing the GJB2 and GJB6 genes coding for connexins 26 and 30, are the most frequent cause of recessive deafness in many populations. We have suggested that the combined eff ...[more]

PMID: 15079193

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Project description:Background: Mutations leading to changes in properties, regulation, or expression of connexin-made channels have been implicated in 28 distinct human hereditary diseases. Eight of these result from variants of connexin 26 (Cx26), a protein critically involved in cell-cell signaling in the inner ear and skin. Lack of non-toxic drugs with defined mechanisms of action poses a serious obstacle to therapeutic interventions for diseases caused by mutant connexins. In particular, molecules that specifically modulate connexin hemichannel function without affecting gap junction channels are considered of primary importance for the study of connexin hemichannel role in physiological as well as pathological conditions. Monoclonal antibodies developed in the last three decades have become the most important class of therapeutic biologicals. Recombinant methods permit rapid selection and improvement of monoclonal antibodies from libraries with large diversity. Methods: By screening a combinatorial library of human single-chain fragment variable (scFv) antibodies expressed in phage, we identified a candidate that binds an extracellular epitope of Cx26. We characterized antibody action using a variety of biochemical and biophysical assays in HeLa cells, organotypic cultures of mouse cochlea and human keratinocyte-derived cells. Results: We determined that the antibody is a remarkably efficient, non-toxic, and completely reversible inhibitor of hemichannels formed by connexin 26 and does not affect direct cell-cell communication via gap junction channels. Importantly, we also demonstrate that the antibody efficiently inhibits hyperative mutant Cx26 hemichannels implicated in autosomal dominant non-syndromic hearing impairment accompanied by keratitis and hystrix-like ichthyosis-deafness (KID/HID) syndrome. We solved the crystal structure of the antibody, identified residues that are critical for binding and used molecular dynamics to uncover its mechanism of action. Conclusions: Although further studies will be necessary to validate the effect of the antibody in vivo, the methodology described here can be extended to select antibodies against hemichannels composed by other connexin isoforms and, consequently, to target other pathologies associated with hyperactive hemichannels. Our study highlights the potential of this approach and identifies connexins as therapeutic targets addressable by screening phage display libraries expressing human randomized antibodies.

Dataset Information

Relevance of connexin deafness (DFNB1) to human evolution.

Publications

Relevance of connexin deafness (DFNB1) to human evolution.

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