Mutation analysis of HPS1, the gene mutated in Hermansky-Pudlak syndrome, in patients with isolated platelet dense-granule deficiency.
نویسندگان
چکیده
BACKGROUND AND OBJECTIVES Isolated platelet dense granule (PDG) deficiency is a heterogeneous disorder frequently found among patients with mild to moderate bleeding diatheses. However, the molecular basis of this disorder is unknown. Genes involved in other rare bleeding disorders with associated reduction in the numbers of platelet dense-granules may play a role in isolated PDG deficiency. Among such genes, HPS1 is known to play a key role in the genesis of PDG and as many as 18 different HPS1 mutations have been identified in patients with Hermansky-Pudlak syndrome. Recently, we have identified subjects with one HPS1 heterozygous mutation displaying significant reductions in PDG without the clinical phenotype of Hermansky-Pudlak syndrome. This suggested that HPS1 mutations could be involved in isolated PDG deficiency. DESIGN AND METHODS We sequenced all coding exons, and flanking intron regions of HPS1 in 16 patients with mild to severe PDG deficiency, most of whom had mild bleeding episodes. Nine patients reported a familial history of bleeding diathesis with PDG deficiency. We also evaluated the prevalence of HPS1 variations in 215 controls. Transmission electron microscopy was used to evaluate the number and morphology of PDG from patients and selected controls. RESULTS No patient with PDG deficiency carried severe mutations of the HPS1 gene. We identified 6 previously described and 5 new polymorphisms in the HPS1 gene. Platelet electron microscopy in controls carrying these polymorphisms revealed that they did not significantly modify the number or morphology of PDG. INTERPRETATION AND CONCLUSIONS Mutations affecting the HPS1 gene play a minor role in isolated PDG deficiency. These results support a molecular heterogeneity responsible for the number and morphology of PDG.
منابع مشابه
A Novel Splice Site Mutation in HPS1 Gene is Associated with Hermansky-Pudlak Syndrome-1 (HPS1) in an Iranian Family
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Hermansky-Pudlak syndrome.
A 55-year-old man had oculocutaneous albinism and a history of frequent bruising following minimal trauma. The simultaneous occurrence of these features was first described by Hermansky and Pudlak in 1959. The Hermansky-Pudlak syndrome follows an autosomal recessive trait and is most frequently found in Puerto Rico and in the Swiss alps. It consists of the triad phenotype of hypopigmentation, p...
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Hermansky-Pudlak syndrome (HPS) is an autosomal recessive condition characterized by a bleeding diathesis and hypopigmentation of the skin, hair, and eyes. Some HPS patients develop other complications such as granulomatous colitis and/or fatal pulmonary fibrosis. Eight genes have been associated with this condition, resulting in subtypes HPS-1 through HPS-8. The HPS gene products are involved ...
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Hermansky-Pudlak syndrome (HPS) defines a group of autosomal recessive disorders characterized by deficiencies in lysosome-related organelles such as melanosomes and platelet-dense granules. Several HPS genes encode proteins of unknown function including HPS1, HPS3, and HPS4. Here we have identified and characterized endogenous HPS3 and HPS4 proteins from HeLa cells. Both proteins were found in...
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عنوان ژورنال:
- Haematologica
دوره 89 3 شماره
صفحات -
تاریخ انتشار 2004