title: A novel CRYAB mutation resulting in multisystemic disease.
abstract: Mutations in the CRYAB gene, encoding alpha-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. To date, multisystemic involvement has been reported only in kindred harboring the R120G substitution. We 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. It has been suggested that the phenotypic diversity could be related to the various interactions between target proteins of individual mutant residues. Molecular modeling 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.
authors.affiliation: Centre de Référence des Maladies Neuromusculaires, Nice Hospital and UMR CNRS6543, Nice University, Nice, France. sacconi@unice.fr
authors.forename: Sabrina
authors.initials: S
authors.lastname: Sacconi
authors.forename: Léonard
authors.initials: L
authors.lastname: Féasson
authors.forename: Jean Christophe
authors.initials: JC
authors.lastname: Antoine
authors.forename: Christophe
authors.initials: C
authors.lastname: Pécheux
authors.forename: Rafaelle
authors.initials: R
authors.lastname: Bernard
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Cobo
authors.forename: Alberto
authors.initials: A
authors.lastname: Casarin
authors.forename: Leonardo
authors.initials: L
authors.lastname: Salviati
authors.forename: Claude
authors.initials: C
authors.lastname: Desnuelle
authors.forename: Andoni
authors.initials: A
authors.lastname: Urtizberea
mesh_terms: D000368:Aged; D009202:Cardiomyopathies / Q000175:diagnosis / Q000235:genetics; D002386:Cataract / Q000175:diagnosis / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D018832:Molecular Chaperones / Q000235:genetics; D009135:Muscular Diseases / Q000175:diagnosis / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D017354:Point Mutation / Q000235:genetics*; D038203:alpha-Crystallin B Chain / Q000737:chemistry / Q000235:genetics*
chemical_list: C059215:CRYAB protein, human; D018832:Molecular Chaperones; D038203:alpha-Crystallin B Chain