RESUMO
Hermansky-Pudlak Syndrome (HPS) is a rare, autosomal recessive disorder that is characterized by oculocutaneous albinism, a predisposition to mild bleeding caused by storage-pool deficient platelets, and a ceroid storage disorder. A gene responsible for HPS in Puerto Rico maps to chromosome 10q2 and isolation of the gene has been reported. We have now identified a variant HPS cDNA that contains the same 5' sequence as the published HPS gene and a unique 3' sequence. Analysis of genomic DNA suggests that the two cDNA are derived from alternative transcripts of a single gene; two polyadenylated transcripts were found in normal human melanocytes, human bone marrow cells, human melanoma cells, lymphoblastoid cell lines, and megakaryocytic leukemia cells by reverse transcriptase polymerase chain reaction and northern analysis. The splicing exhibited by this gene is identical to the splicing found to produce two alternative transcripts of the Chediak-Higashi Syndrome gene, another pigment disorder exhibiting platelet storage pool deficiency. These studies show that the HPS gene on chromosome 10 is complex and may have more than one biologically active transcript.
Assuntos
Albinismo Oculocutâneo/genética , Transcrição Gênica , Sequência de Aminoácidos , Sequência de Bases , Mapeamento Cromossômico , Cromossomos Humanos Par 10/genética , DNA Complementar/genética , Variação Genética/genética , Humanos , Dados de Sequência Molecular , Mutação/genética , Deficiência do Pool Plaquetário/genética , Porto Rico , RNA Mensageiro/metabolismo , Transcrição Gênica/fisiologiaRESUMO
Hermansky-Pudlak syndrome (HPS) consists of ocu-locutaneous albinism, a platelet storage-pool deficiency, and ceroid lipofuscinosis. In a recent report on the cloning of an HPS gene, all 22 Puerto Rican HPS patients were homozygous for a 16-bp duplication in exon 15. This presumably reflected a founder effect for the HPS mutation in Puerto Rico. Nevertheless, we ascertained two individuals from central Puerto Rico who lacked the 16-bp duplication, exhibited significant amounts of normal-size HPS mRNA by northern blot analysis, and had haplotypes in the HPS region that were different from the haplotype of every 16-bp-duplication patient. Moreover, these two individuals displayed no mutations in their cDNA sequences, throughout the entire HPS gene. Both patients exhibited pigment dilution, impaired visual acuity, nystagmus, a bleeding diathesis, and absent platelet dense bodies, confirming the diagnosis of HPS. These findings indicate that analysis of Puerto Rican patients for the 16-bp duplication in HPS cannot exclude the diagnosis of HPS. In addition, HPS most likely displays locus heterogeneity, consistent with the existence of several mouse strains manifesting both pigment dilution and a platelet storage-pool deficiency.
Assuntos
Albinismo Oculocutâneo/genética , Heterogeneidade Genética , Albinismo Oculocutâneo/diagnóstico , Alelos , Plaquetas/ultraestrutura , Northern Blotting , Pré-Escolar , Análise Mutacional de DNA , Primers do DNA , Eletroforese em Gel de Ágar , Feminino , Haplótipos/genética , Humanos , Masculino , Microscopia Eletrônica , Pessoa de Meia-Idade , Pigmentação/genética , Deficiência do Pool Plaquetário/diagnóstico , Deficiência do Pool Plaquetário/genética , Reação em Cadeia da Polimerase , Porto Rico , Sequências Repetitivas de Ácido Nucleico/genéticaRESUMO
Hermansky-Pudlak syndrome (HPS) is an autosomal recessive disorder that affects pigment production and platelet function and causes the deposition of a ceroid-like material in various tissues. Variability in the phenotype and the presence of several potential mouse models suggest that HPS may be a heterogeneous disorder. In order to identify a gene responsible for HPS, we collected blood samples from a relatively homogeneous population in Puerto Rico where the HPS carrier frequency is estimated to be 1 in 21. Analysis of pooled DNA samples allowed us to rapidly screen the genome for candidate loci, and significant evidence for linkage was detected for a marker on chromosome 10q. This region of the human genome is conserved syntenically with the region on mouse chromosome 19 where two possible mouse models for HPS, pale ear and ruby eye, are located. This linkage result was verified with additional markers, and a maximum LOD score of 5.07 at theta = .001 was calculated for marker D10S198. Haplotype analysis places the HPS gene in a region of approximately 14 cM that contains the markers D10S198 and D10S1239.