RESUMEN
INTRODUCTION: Inherited macrothrombocytopenia represents a heterogeneous group of disorders which are characterized by the presence of a reduced number of abnormally large platelets in the circulation, which may or may not be associated with a bleeding tendency. In spite of several causative genes having been identified, the underlying genetic defects remain to be identified in approximately half of the cases. AIMS: To understand the molecular pathology of isolated giant platelet disorder from India. MATERIALS AND METHODS: We studied 112 cases that were referred for investigation of macrothrombocytopenia. Agonist induced platelet aggregation and platelet GP1b/IX/V receptor expression were investigated to assess GP1b/IX/V receptor expression and the GP1BA, GP1BB, GP9, ABCG5, ABCG8, TUBB1 and MYH9 genes were analysed to identify candidate gene defects. RESULTS: Twenty-three candidate gene defects were identified in 48 of 112 cases, 20 of which were novel. Of the candidate defects identified, 91% were missense and 9% were nonsense variations. The missense variations were in GP9 (9), ABCG5 (4), GP1BB (3), GP1BA (3) and MYH9 (2), while the nonsense defects occurred in MYH9 (1) and GP1BA (1). CONCLUSIONS: This study increases the understanding of the molecular basis of an isolated giant platelet disorder, a common heterogeneous condition prevalent in north and eastern India.
Asunto(s)
Enfermedades Genéticas Ligadas al Cromosoma X/diagnóstico , Complejo GPIb-IX de Glicoproteína Plaquetaria/metabolismo , Trombocitopenia/diagnóstico , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 5/genética , Adolescente , Adulto , Anciano , Pruebas de Coagulación Sanguínea , Plaquetas/citología , Plaquetas/metabolismo , Niño , Codón sin Sentido , Femenino , Estudios de Asociación Genética , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Genotipo , Hemorragia/etiología , Heterocigoto , Humanos , India , Lipoproteínas/genética , Masculino , Persona de Mediana Edad , Proteínas Motoras Moleculares/genética , Mutación Missense , Cadenas Pesadas de Miosina/genética , Fenotipo , Complejo GPIb-IX de Glicoproteína Plaquetaria/genética , Polimorfismo de Nucleótido Simple , Trombocitopenia/congénito , Trombocitopenia/genética , Adulto JovenRESUMEN
BACKGROUND AND OBJECTIVES: Locus heterogeneity is well established in autosomal recessive primary microcephaly (MCPH) and to date five loci have been mapped. However, the relative contributions of these loci have not been assessed and genotype-phenotype correlations have not been investigated. DESIGN: A study population of 56 consanguineous families resident in or originating from northern Pakistan was ascertained and assessed by the authors. A panel of microsatellite markers spanning each of the MCPH loci was designed, against which the families were genotyped. RESULTS: The head circumference of the 131 affected subjects ranged from 4 to 14 SD below the mean, but there was little intrafamilial variation among affecteds (+/- 1 SD). MCPH5 was the most prevalent, with 24/56 families consistent with linkage; 2/56 families were compatible with linkage to MCPH1, 10/56 to MCPH2, 2/56 to MCPH3, none to MCPH4, and 18/56 did not segregate with any of the loci. CONCLUSIONS: MCPH5 is the most common locus in this population. On clinical grounds alone, the phenotype of families linked to each MCPH locus could not be distinguished. We have also shown that further MCPH loci await discovery with a number of families as yet unlinked.
Asunto(s)
Genes Recesivos/genética , Heterogeneidad Genética , Marcadores Genéticos/genética , Variación Genética/genética , Microcefalia/genética , Adolescente , Adulto , Niño , Preescolar , Consanguinidad , Femenino , Humanos , Lactante , Recién Nacido , Discapacidad Intelectual/genética , Masculino , Repeticiones de Microsatélite/genética , Persona de Mediana Edad , FenotipoRESUMEN
Kufor-Rakeb syndrome is an autosomal recessive nigro-striatal-pallidal-pyramidal neurodegeneration. The onset is in the teenage years with clinical features of Parkinson's disease plus spasticity, supranuclear upgaze paresis, and dementia. Brain scans show atrophy of the globus pallidus and pyramids and, later, widespread cerebral atrophy. We report linkage in Kufor-Rakeb syndrome to a 9 cM region of chromosome 1p36 delineated by the markers D1S436 and D1S2843, with a maximum multipoint lod score of 3.6.