RESUMO
OBJECTIVE: To identify the pathogenic mutation underlying piebaldism in a Chinese family. METHODS: A three-generation family showing an autosomal dominant transmission of piebaldism was recruited. Potential mutations of the KIT and SNAI2 genes were detected by PCR-amplification of the exons and exon-intron boundaries and direct sequencing. RESULTS: A heterozygous missense mutation, c.2585T>C, was identified in exon 18 of the KIT gene. The mutation, together with a c.2586G>C polymorphism, has led to substitution of Leucine by Proline at amino acid residue 862 (p.Leu862Pro) of the mast/stem cell growth factor receptor KIT. The same mutation was detected in all affected family members but not in dbSNP142, the 1000 Genomes draft database, or the Human Gene Mutation Database. No mutation of the SNAI2 gene was found. CONCLUSION: The c.2585T>C (p.Leu862Pro) mutation in the KIT gene probably underlies the piebaldism phenotype in this family.
Assuntos
Predisposição Genética para Doença/genética , Mutação de Sentido Incorreto , Piebaldismo/genética , Proteínas Proto-Oncogênicas c-kit/genética , Sequência de Aminoácidos , Povo Asiático/genética , Sequência de Bases , China , Análise Mutacional de DNA/métodos , Éxons/genética , Saúde da Família , Feminino , Predisposição Genética para Doença/etnologia , Heterozigoto , Humanos , Lactente , Íntrons/genética , Masculino , Linhagem , Fenótipo , Piebaldismo/etnologia , Reação em Cadeia da Polimerase , Polimorfismo de Nucleotídeo Único , Homologia de Sequência de AminoácidosRESUMO
The RAB27A/Melanophilin/Myosin-5a tripartite protein complex is required for capturing mature melanosomes in the peripheral actin network of melanocytes for subsequent transfer to keratinocytes. Mutations in any one member of this tripartite complex cause three forms of Griscelli syndrome (GS), each with distinct clinical features but with a similar cellular phenotype. To date, only one case of GS type III (GSIII), caused by mutations in the Melanophilin (MLPH) gene, has been reported. Here, we report seven new cases of GSIII in three distinct Arab pedigrees. All affected individuals carried a homozygous missense mutation (c.102C>T; p.R35W), located in the conserved Slp homology domain of MLPH, and had hypomelanosis of the skin and hair. We report the first cellular studies on GSIII melanocytes, which demonstrated that MLPH(R35W) causes perinuclear aggregation of melanosomes in melanocytes, typical for GS. Additionally, co-immunoprecipitation assays showed that MLPH(R35W) lost its interaction with RAB27A, indicating pathogenicity of the R35W mutation.
