RESUMO
Autosomal recessive Charcot-Marie-Tooth disease type 4B (CMT4B) is a demyelinating hereditary motor and sensory neuropathy characterized by abnormal folding of myelin sheaths. A locus for CMT4B has previously been mapped to chromosome 11q23 in a southern Italian pedigree. We initially excluded linkage in two Tunisian families with CMT4B to chromosome 11q23, demonstrating genetic heterogeneity within the CMT4B phenotype. Subsequently, using homozygosity mapping and linkage analysis in the largest Tunisian pedigree, we mapped a new locus to chromosome 11p15. A maximum two-point lod score of 6.05 was obtained with the marker D11S1329. Recombination events refined the CMT4B locus region to a 5.6-cM interval between markers D11S1331 and D11S4194. The second Tunisian CMT4B family was excluded from linkage to the new locus, demonstrating the existence of at least a third locus for the CMT4B phenotype.
Assuntos
Doença de Charcot-Marie-Tooth/genética , Cromossomos Humanos Par 11/genética , Genes Recessivos , Bainha de Mielina/genética , Dobramento de Proteína , Mapeamento Cromossômico , Consanguinidade , Feminino , Ligação Genética , Marcadores Genéticos , Testes Genéticos , Genótipo , Haplótipos , Humanos , Escore Lod , Masculino , Condução Nervosa/genética , Linhagem , Fenótipo , TunísiaRESUMO
Autosomal recessive muscular dystrophy is genetically heterogeneous. One form of this disorder, limb-girdle muscular dystrophy type 2C (LGMD 2C), is prevalent in northern Africa and has been shown to be associated with a single mutation in the gene encoding the dystrophin-associated protein gamma-sarcoglycan. The previous mutation analysis of gamma-sarcoglycan required the availability of muscle biopsies. To establish a mutation assay for genomic DNA, the intron-exon structure of the gamma-sarcoglycan gene was determined, and primers were designed to amplify each of the exons encoding gamma-sarcoglycan. We studied a group of Brazilian muscular dystrophy patients for mutations in the gamma-sarcoglycan gene. These patients were selected on the basis of autosomal inheritance and/or the presence of normal dystrophin and/or deficiency of alpha-sarcoglycan immunostaining. Four of 19 patients surveyed had a single, homozygous mutation in the gamma-sarcoglycan gene. The mutation identified in these patients, all of African-Brazilian descent, is identical to that seen in the North African population, suggesting that even patients of remote African descent may carry this mutation. The phenotype in these patients varied considerably. Of four families with an identical mutation, three have a severe Duchenne-like muscular dystrophy. However, one family has much milder symptoms, suggesting that other loci may be present that modify the severity of the clinical course resulting from gamma-sarcoglycan gene mutations.
Assuntos
Proteínas do Citoesqueleto , Glicoproteínas de Membrana/genética , Distrofias Musculares/genética , Adolescente , Adulto , África do Norte/etnologia , Brasil/epidemiologia , Criança , Feminino , Humanos , Masculino , Dados de Sequência Molecular , Distrofias Musculares/etnologia , Linhagem , Mutação Puntual , Polimorfismo Genético , SarcoglicanasAssuntos
Doença de Charcot-Marie-Tooth/classificação , Doença de Charcot-Marie-Tooth/genética , Neuropatias Hereditárias Sensoriais e Autônomas/classificação , Neuropatias Hereditárias Sensoriais e Autônomas/genética , Doença de Charcot-Marie-Tooth/diagnóstico , Cromossomos Humanos Par 3/genética , Feminino , Ligação Genética , Neuropatias Hereditárias Sensoriais e Autônomas/diagnóstico , Humanos , Escore Lod , MasculinoRESUMO
We have previously localized one form of the autosomal recessive Charcot-Marie-Tooth disease type 4 (CMT4A) to a 5-cM region of chromosome 8q13-q21. We now report the formation of a 7-Mb YAC contig spanning the region. This contig was used to map nine additional microsatellites and six STSs to this region, and subsequent haplotype analysis has narrowed the CMT4A flanking interval to less than 1 cM. In addition, using SSCP and our physical map, we have demonstrated that the myelin protein PMP-2, mapped by FISH to this region, is not the defect in CMT4A.
