Prelingual non-syndromic (isolated) deafness is the most frequent hereditary sensory defect. In >80% of the cases, the mode of transmission is autosomal recessive. To date, 14 loci have been identified for the recessive forms (DFNB loci). For two of them, DFNB1 and DFNB2, the genes responsible have been characterized; they encode connexin 26 and myosin VIIA, respectively. In order to evaluate the extent to which the connexin 26 gene (Cx26) contributes to prelingual deafness, we searched for mutations in this gene in 65 affected Caucasian families originating from various countries, mainly tunisia, France, New Zealand and the UK. Six of these families are consanguineous, and deafness was shown to be linked to the DFNB1 locus, 10 are small non consanguineous families in which the segregation of the trait has been found to be compatible with the involvement of DFNB1, and in the remaining 49 families no linkage analysis has been performed. A total of 62 mutant alleles in 39 families were identified. Therefore, mutations in Cx26 represent a major cause of recessively inherited prelingual deafness since according to the present results they would underlie approximately half of the cases. In addition, one specific mutation, 30delG, accounts for the majority (approximately 70%) of the Cx26 mutant alleles. It is therefore one of the most frequent disease mutations so far identified. Several lines of evidence indicate that the high prevalence of the 30delG mutation arises from a mutation hot spot rather than from a founder effect. Genetic counseling for prelingual deafness has been so far considerably impaired by the difficulty in distinguishing genetic and non genetic deafness in families presenting with a single deaf child. Based on the results presented here, the development of a simple molecular test could be designed which should be of considerable help.

Small stress proteins are developmentally regulated and linked to cell growth and differentiation. The early phase of murine embryonic stem (ES) cell differentiation, characterized by a gradual growth arrest, is accompanied with hsp27 transient accumulation. This differentiation process also correlated with changes in hsp27 phosphorylation and oligomerization. The role of hsp27 was investigated in ES clones stably transfected with murine or human hsp27 genes, placed in sense or antisense orientation. Several clones were obtained that either underexpressed endogenous murine hsp27 or overexpressed murine or human hsp27. Maintained undifferentiated, these clones showed similar growth rates. We report here that hsp27 constitutive overexpression enhanced the differentiation-mediated decreased rate of ES cell proliferation but did not alter morphological changes. In contrast, hsp27 underexpression, which attenuated cell growth arrest, induced differentiation abortion because of an overall cell death by apoptosis. Recently, we showed that hsp27 interfered with cell death probably because of its ability to modulate intracellular glutathione. hsp27 accumulation during ES cell differentiation was also correlated with an increase in glutathione, which was attenuated by hsp27 down-expression. Hence, hsp27 transient expression seems essential for preventing differentiating ES cells from undergoing apoptosis, a switch that may be redox regulated.Mammalian hsp27 belongs to the family of small heat shock proteins (SHSP) 1 that are characterized by a strong homology to lens ␣-crystallin (reviewed in Ref. 1). SHSP share the ability to form oligomeric structures (2, 3) and are often detected as phosphoproteins (4, 5). Many stimuli, such as serum, oxidative injury, thermal stress, inflammatory cytokines (tumor necrosis factor-␣, interleukin-1), and retinoic acid have been described as potent modulators of mammalian hsp27 phosphorylation and oligomerization (reviewed in Ref. 1). SHSP expression was shown to protect against cell necrosis induced by stimuli such as hyperthermia (6, 7), anti-cancerous drugs, oxidative stress (7-10), and inflammatory cytokines (9, 11). Recently, we reported that SHSP are also negative regulators of apoptosis that counteract Fas/APO-1 or staurosporine-induced programmed cell death (12).To explain the protective activity of SHSP, it has been proposed that these proteins act as molecular chaperones (13) or actin capping/decapping enzymes (14, 15). In addition, we recently reported that the expression of SHSP from different species induced an increase in glutathione that resulted in a decreased level of intracellular reactive oxygen species (ROS) (10). This conserved property was found to be essential for the protective activity of SHSP against oxidative stress-or tumor necrosis factor-␣-induced cell death.An interesting feature of SHSP concerns their transient expression during development and cell differentiation. This was first observed in Drosophila (reviewed in Ref. 16), and studies performed in other ...