Résumé :
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Mutations in the CRYAB gene, encoding _B-crystallin, cause distinct clinical phenotypes including isolated posterior polar cataract, myofibrillar myopathy, cardiomyopathy, or a multisystemic disorder combining all these features. Genotype/phenotype correlations are still unclear. However, mutations affecting exon 1 are known to cause isolated cataracts, while those in exon 3 may be associated with any of the above-mentioned phenotypes.To date, multisystemic involvement has been reported only in French kindred harbouring the R120G substitution. We now report a novel CRYAB mutation, D109H, associated with posterior polar cataract, myofibrillar myopathy and cardiomyopathy in a two-generation family with five affected individuals. Age of onset, clinical presentation, and muscle abnormalities were very similar to those described in the R120G family. Alpha-B-crystallin may form dimers and acts as a chaperone for a number of proteins including desmin and titin. It has been suggested that the phenotypic diversity could be related to the various interactions between target proteins of individual mutant residues.Molecular modelling indicates that residues D109 and R120 interact with each other during dimerization of (alpha)B-crystallin; interestingly, the two substitutions affecting these residues (D109H and R120G) are associated with the same clinical phenotype, thus suggesting a similar pathogenic mechanism. We propose that impairment of (alpha)B-crystallin dimerization may also be relevant to the pathogenesis of these disorders.
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