RESUMEN
During the recent cloning of the mouse Lyst gene we developed both a high-resolution genetic map and a complete YAC and BAC contig of the Lyst critical region on mouse Chromosome 13. We also report the mapping of the human homologue of the mouse Lyst gene (LYST) to 1q43. These data are consistent with LYST being the gene for the human Chediak-Higashi Syndrome and strengthen the synteny relationship between MMU13 and human 1q43.
Asunto(s)
Mapeo Cromosómico , Proteínas/genética , Animales , Secuencia de Bases , Cromosomas Humanos Par 1 , ADN Complementario , Femenino , Humanos , Péptidos y Proteínas de Señalización Intracelular , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Datos de Secuencia Molecular , Proteínas de Transporte VesicularRESUMEN
Chediak-Higashi syndrome (CHS) is a rare, autosomal recessive disorder characterized by hypopigmentation, severe immunologic deficiency with neutropenia and lack of natural killer (NK) cells, a bleeding tendency and neurologic abnormalities. Most patients die in childhood. The CHS hallmark is the occurrence of giant inclusion bodies and organelles in a variety of cell types, and protein sorting defects into these organelles. Similar abnormalities occur in the beige mouse, the proposed model for human CHS. Two groups have recently reported the identification of the beige gene, however the two cDNAs were not at all similar. Here we describe the sequence of a human cDNA homologous to mouse beige, identify pathologic mutations and clarify the discrepancies of the previous reports. Analysis of the CHS polypeptide demonstrates that its modular architecture is similar to the yeast vacuolar sorting protein, VPS15.
Asunto(s)
Síndrome de Chediak-Higashi/genética , Análisis Mutacional de ADN , Proteínas/genética , Adulto , Empalme Alternativo , Secuencia de Aminoácidos , Animales , Clonación Molecular , Complejos de Clasificación Endosomal Requeridos para el Transporte , Femenino , Homocigoto , Humanos , Lactante , Péptidos y Proteínas de Señalización Intracelular , Masculino , Ratones , Modelos Moleculares , Datos de Secuencia Molecular , Sistemas de Lectura Abierta , Conformación Proteica , Proteínas Serina-Treonina Quinasas/genética , Proteínas/química , Homología de Secuencia de Aminoácido , Proteína de Clasificación Vacuolar VPS15 , Proteínas de Transporte VesicularRESUMEN
The beige mutation is a murine autosomal recessive disorder, resulting in hypopigmentation, bleeding and immune cell dysfunction. The gene defective in beige is thought to be a homologue of the gene for the human disorder Chediak-Higashi syndrome. We have identified the murine beige gene by in vitro complementation and positional cloning, and confirmed its identification by defining mutations in two independent mutant alleles. The sequence of the beige gene message shows strong nucleotide homology to multiple human ESTs, one or more of which may be associated with the Chediak-Higashi syndrome gene. The amino acid sequence of the Beige protein revealed a novel protein with significant amino acid homology to orphan proteins identified in Saccharomyces cerevisiae, Caenorhabditis elegans and humans.
Asunto(s)
Síndrome de Chediak-Higashi/genética , Mutación , Proteínas/genética , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Mapeo Cromosómico , Cromosomas Artificiales de Levadura , Clonación Molecular/métodos , Prueba de Complementación Genética , Humanos , Péptidos y Proteínas de Señalización Intracelular , Ratones , Ratones Endogámicos , Ratones Mutantes , Datos de Secuencia Molecular , Biosíntesis de Proteínas , Proteínas/química , Análisis de Secuencia de ADN , Homología de Secuencia de Aminoácido , Proteínas de Transporte VesicularRESUMEN
The mutated gene responsible for the tubby obesity phenotype has been identified by positional cloning. A single base change within a splice donor site results in the incorrect retention of a single intron in the mature tub mRNA transcript. The consequence of this mutation is the substitution of the carboxy-terminal 44 amino acids with 24 intron-encoded amino acids. The normal transcript appears to be abundantly expressed in the hypothalamus, a region of the brain involved in body weight regulation. Variation in the relative abundance of alternative splice products is observed between inbred mouse strains and appears to correlate with an intron length polymorphism. This allele of tub is a candidate for a previously reported diet-induced obesity quantitative trait locus on mouse chromosome 7.