Making connections with mitochondria?

Abstract

Two recent papers have revealed a remarkable involvement of a single human gene, GJB3, in two apparently distinct disorders: progressive hearing loss 1 X J.H. et al. Mutations in the gene encoding gap junction protein beta-3 associated with autosomal dominant hearing impairment. Nat. Genet. 1998; 20: 370-373 Crossref PubMed Scopus (380) Google Scholar and a form of hyperkeratosis, Erythrokeratodermia variabilis2 Richard G. et al. Mutations in the human connexin gene GJB3 cause erythrokeratodermia variabilis. Nat. Genet. 1998; 20: 366-369 Crossref PubMed Scopus (299) Google Scholar . The gene encodes connexin 31, a member of a large family of gap junction-forming proteins, two other members of which have already been implicated in both dominant and recessive forms of syndromic and non-syndromic deafness. The precise mechanisms by which different connexin mutations produce these two pathological phenotypes remain to be elucidated, but a further remarkable connection between deafness and a hyperkeratotic disorder is provided by the NP7445 mitochondrial DNA mutation. Sevior et al.3 Sevior K.B. et al. Mitochondrial A7445G mutation in two pedigrees with palmoplantar keratoderma and deafness. Am. J. Med. Genet. 1998; 75: 179-185 Crossref PubMed Scopus (118) Google Scholar found that this mutation was associated with a combined phenotype of progressive hearing loss and palmoplantar keratoderma in two different maternal pedigrees, one from New Zealand, the other from Japan. The same applies to the Scottish family in which the mutation was first reported (G.A. Vernham et al., unpublished), indicating that the association is robust. Mutations in connexins and in mtDNA can result in superficially similar types of deafness, although no detail on the exact cellular or developmental abnormalities arising from either is yet available. The fact that both are also associated with forms of hyperkeratosis strongly suggests a common mechanism. One possibility is that various types of epithelial cell function or patterning require propagation of an ionic signal across a cell sheet, an obvious candidate being calcium. Gap junctions would transmit such a signal between cells, whereas properly energized mitochondria would be required to transmit the signal across each single cell. It is already known that mitochondria can transduce and amplify calcium waves across cells in a manner dependent on respiratory energy 4 Ichas F. et al. Mitochondria are excitable organelles capable of generating and conveying electrical and calcium signals. Cell. 1997; 89: 1145-1153 Abstract Full Text Full Text PDF PubMed Scopus (646) Google Scholar . Even if this hypothesis is correct, many mysteries remain, not least of which is the question of why only a subset of mtDNA mutations affecting protein synthesis results in deafness, and why only one, so far, is involved also in hyperkeratosis. Until recently, this type of feature was widely regarded as a peculiarity of mitochondrial genetics. The connexin phenotypes illustrate the fact that this is really a more general property of human disease mutations.