RESUMO
We took advantage of overlapping interstitial deletions at chromosome 8p11-p12 in two individuals with contiguous gene syndromes and defined an interval of roughly 540 kb associated with a dominant form of Kallmann syndrome, KAL2. We establish here that loss-of-function mutations in FGFR1 underlie KAL2 whereas a gain-of-function mutation in FGFR1 has been shown to cause a form of craniosynostosis. Moreover, we suggest that the KAL1 gene product, the extracellular matrix protein anosmin-1, is involved in FGF signaling and propose that the gender difference in anosmin-1 dosage (because KAL1 partially escapes X inactivation) explains the higher prevalence of the disease in males.
Assuntos
Proteínas da Matriz Extracelular , Síndrome de Kallmann/genética , Mutação , Receptores Proteína Tirosina Quinases/genética , Receptores de Fatores de Crescimento de Fibroblastos/genética , Moléculas de Adesão Celular/metabolismo , Deleção Cromossômica , Cromossomos Humanos Par 8 , Cromossomos Humanos X , Éxons , Matriz Extracelular/metabolismo , Saúde da Família , Feminino , Genes Dominantes , Humanos , Íntrons , Masculino , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Linhagem , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos , Fatores Sexuais , Transdução de SinaisRESUMO
We report on a novel localization for a recessive form of deafness (DFNB), by linkage analysis in an Iranian consanguineous family. Affected individuals suffer from prelingual profound sensorineural hearing loss. Genome-wide analysis led to the characterization of a new locus, DFNB40, which maps to an approximately 9 Mb interval between markers D22S427 and D22S1144 at chromosome 22q11.21-12.1. Maximum lod score of 3.09 was obtained with D22S1174. Since the Bronx waltzer (bv) mouse mutant, characterized by waltzing behavior, deafness, and degeneration of cochlear inner hair cells, has been mapped to the syntenic region on murine chromosome 5, we suggest that DFNB40 and bv may result from orthologous gene defects.