Hermansky-Pudlak syndrome（HPS） is a recessive disorder with bleeding diathesis, which has been linked to platelet granule defects. Both platelet granules and endothelial Weibel-Palade bodies（WPBs）are members of ly...Hermansky-Pudlak syndrome（HPS） is a recessive disorder with bleeding diathesis, which has been linked to platelet granule defects. Both platelet granules and endothelial Weibel-Palade bodies（WPBs）are members of lysosome-related organelles（LROs） whose formation is regulated by HPS protein associated complexes such as BLOC（biogenesis of lysosome-related organelles complex）-1,-2,-3, AP-3（adaptor protein complex-3） and HOPS（homotypic fusion and protein sorting complex）. Von Willebrand factor（VWF） is critical to hemostasis, which is stored in a highly-multimerized form as tubules in the WPBs. In this study, we found the defective, but varying, release of VWF into plasma after desmopressin（DDAVP） stimulation in HPS1（BLOC-3 subunit）, HPS6（BLOC-2 subunit）, and HPS9（BLOC-1 subunit）deficient mice. In particular, VWF tubulation, a critical step in VWF maturation, was impaired in HPS6 deficient WPBs. This likely reflects a defective endothelium, contributing to the bleeding tendency in HPS mice or patients. The differentially defective regulated release of VWF in these HPS mouse models suggests the need for precise HPS genotyping before DDAVP administration to HPS patients.展开更多
BACKGROUND Hermansky-Pudlak syndrome(HPS)is a rare autosomal recessive disorder characterized by oculocutaneous albinism,platelet storage pool deficiency and systemic complications associated with ceroid deposition in...BACKGROUND Hermansky-Pudlak syndrome(HPS)is a rare autosomal recessive disorder characterized by oculocutaneous albinism,platelet storage pool deficiency and systemic complications associated with ceroid deposition in the reticuloendothelial system.HPS types 1 and 4 are associated with Crohn’s disease(CD)-like gastrointestinal disorders,such as granulomatous enterocolitis or perianal disease.Cases of colitis can be particularly severe and,before the use of anti-tumor necrosis factor alpha(TNFα)therapy had become common,were reported as showing poor responsiveness to medical treatment.CASE SUMMARY We present the case of a 51-year-old albino woman who presented with acute severe colitis that led to the diagnosis of HPS.Histologic findings of biopsy samples showed chronic inflammation with deep ulcerations,and granulomas without caseous necrosis.Molecular genetic analysis confirmed HPS type 1,with a homozygous 27 base-pair deletion in exon 20 of the HPS1 gene.Once the patient’s bleeding diathesis was corrected by platelet transfusion,the granulomatous colitis responded dramatically to a medical treatment regimen that included corticosteroids,azathioprine and infliximab;this regimen is similar to that used in CD treatment.Although it remains unclear if the granulomatous enterocolitis in HPS is due to ceroid deposition or reflects the co-existence of CD and HPS,the fact that this case of HPS-related granulomatous colitis responded to the same therapeutic approach used in CD suggests that this type of colitis may result from HPS patients’genetic susceptibility to CD.CONCLUSION We report a case of severe colitis that led to the diagnosis of HPS,which was responsive to azathioprine and infliximab.展开更多
With the identification of more than a dozen novel Hermansky-Pudlak Syndrome （HPS） proteins in vesicle trafficking in higher eukaryotes, a new class of trafficking pathways has been described. It mainly consists of ...With the identification of more than a dozen novel Hermansky-Pudlak Syndrome （HPS） proteins in vesicle trafficking in higher eukaryotes, a new class of trafficking pathways has been described. It mainly consists of three newly-defined protein com- plexes, BLOC-l, -2, and -3. Compelling evidence indicates that these complexes together with two other well-known complexes, AP3 and HOPS, play important roles in endosomal transport. The interactions between these complexes form a network in protein trafficking via endosomes and cytoskeleton. Each node of this network has intra-complex and extra-complex interactions. These complexes are connected by direct interactions between the subunits from different complexes or by indirect interactions through coupling nodes that interact with two or more subunits from different complexes. The dissection of this network facilitates the understanding of a dynamic but elaborate transport machinery in protein/membrane trafficking. The disruption of this network may lead to abnormal trafficking or defective organellar development as described in patients with Hermansky-Pudlak syndrome.展开更多
A 10-year-old Chinese boy who had a history of congenital thrombocytopathy presented with severe iron deficiency anemia secondary to chronic gastric inflammation and duodenal ulcerations. Subtle oculocutaneous albinis...A 10-year-old Chinese boy who had a history of congenital thrombocytopathy presented with severe iron deficiency anemia secondary to chronic gastric inflammation and duodenal ulcerations. Subtle oculocutaneous albinism led to the finding of diminished dense bodies in the platelets under electron microscopy, hence the diagnosis of Hermansky-Pudlak syndrome (HPS). Biopsies from the stomach and duodenum revealed a lymphocytic infiltration in the submucosa, but H pylori infection was absent. The gastroduodenitis responded to the treatment with omeprazole while iron deficiency anemia was corrected by oral iron therapy. HPS is a rare cause of congenital bleeding disorder with multisystemic manifestations. Upper gastrointestinal involvement is rare and should be distinguished from a mere manifestation of the bleeding diathesis.展开更多
Hermansky-Pudlak syndrome (HPS) is an autosomal recessive disorder characterized by oculocutaneous albinism(OCA), bleeding tendency, and lysosomal accumulation of ceroid-like material. Seven genetically distinct subty...Hermansky-Pudlak syndrome (HPS) is an autosomal recessive disorder characterized by oculocutaneous albinism(OCA), bleeding tendency, and lysosomal accumulation of ceroid-like material. Seven genetically distinct subtypes of HPS are known in humans; most are rare outside of Puerto Rico. Here, we describe the analysis of the HPS1 gene in 24 Japanese OCA patients who lacked mutations in the four genes known to cause OCA (TYR/OCA1, P/OCA2, TVRP1/OCA3, and MATP/OCA4), and the identification of eight different HPS1 mutations in ten of these patients, four of which were novel (W583X,L668P, 532insC,1691delA).An IVS5 + 5G→ A splice consensus mutation was particularly frequent, the result of a founder effect for this allele in Japanese patients. Functional analysis by transfection of the L668P variant into Hps1-mutant melanep mouse melanocytes showed that this missense substitution is pathologic, resulting in an Hps-1 protein that is unable to assemble into the biogenesis of lysosome-related organelles complex-3.展开更多
基金partially supported by the grants from the National Natural Science Foundation of China(Nos.91539204 and 31230046)the Ministry of Science and Technology of China(No.2013CB530605)(to W.L.)from MRC of UK(MC-UU-12018/2,to D.C.)
文摘Hermansky-Pudlak syndrome（HPS） is a recessive disorder with bleeding diathesis, which has been linked to platelet granule defects. Both platelet granules and endothelial Weibel-Palade bodies（WPBs）are members of lysosome-related organelles（LROs） whose formation is regulated by HPS protein associated complexes such as BLOC（biogenesis of lysosome-related organelles complex）-1,-2,-3, AP-3（adaptor protein complex-3） and HOPS（homotypic fusion and protein sorting complex）. Von Willebrand factor（VWF） is critical to hemostasis, which is stored in a highly-multimerized form as tubules in the WPBs. In this study, we found the defective, but varying, release of VWF into plasma after desmopressin（DDAVP） stimulation in HPS1（BLOC-3 subunit）, HPS6（BLOC-2 subunit）, and HPS9（BLOC-1 subunit）deficient mice. In particular, VWF tubulation, a critical step in VWF maturation, was impaired in HPS6 deficient WPBs. This likely reflects a defective endothelium, contributing to the bleeding tendency in HPS mice or patients. The differentially defective regulated release of VWF in these HPS mouse models suggests the need for precise HPS genotyping before DDAVP administration to HPS patients.
文摘BACKGROUND Hermansky-Pudlak syndrome(HPS)is a rare autosomal recessive disorder characterized by oculocutaneous albinism,platelet storage pool deficiency and systemic complications associated with ceroid deposition in the reticuloendothelial system.HPS types 1 and 4 are associated with Crohn’s disease(CD)-like gastrointestinal disorders,such as granulomatous enterocolitis or perianal disease.Cases of colitis can be particularly severe and,before the use of anti-tumor necrosis factor alpha(TNFα)therapy had become common,were reported as showing poor responsiveness to medical treatment.CASE SUMMARY We present the case of a 51-year-old albino woman who presented with acute severe colitis that led to the diagnosis of HPS.Histologic findings of biopsy samples showed chronic inflammation with deep ulcerations,and granulomas without caseous necrosis.Molecular genetic analysis confirmed HPS type 1,with a homozygous 27 base-pair deletion in exon 20 of the HPS1 gene.Once the patient’s bleeding diathesis was corrected by platelet transfusion,the granulomatous colitis responded dramatically to a medical treatment regimen that included corticosteroids,azathioprine and infliximab;this regimen is similar to that used in CD treatment.Although it remains unclear if the granulomatous enterocolitis in HPS is due to ceroid deposition or reflects the co-existence of CD and HPS,the fact that this case of HPS-related granulomatous colitis responded to the same therapeutic approach used in CD suggests that this type of colitis may result from HPS patients’genetic susceptibility to CD.CONCLUSION We report a case of severe colitis that led to the diagnosis of HPS,which was responsive to azathioprine and infliximab.
基金This work was supported in part by the National Science Fund for Distinguished Young Scholars (No. 30525007)National Basic Research Program of China (No. 2006CB504103+1 种基金 No. 2006CB500704)Hi-Tech Research and Development Program of China (No. 2006AA02Z322)
文摘With the identification of more than a dozen novel Hermansky-Pudlak Syndrome （HPS） proteins in vesicle trafficking in higher eukaryotes, a new class of trafficking pathways has been described. It mainly consists of three newly-defined protein com- plexes, BLOC-l, -2, and -3. Compelling evidence indicates that these complexes together with two other well-known complexes, AP3 and HOPS, play important roles in endosomal transport. The interactions between these complexes form a network in protein trafficking via endosomes and cytoskeleton. Each node of this network has intra-complex and extra-complex interactions. These complexes are connected by direct interactions between the subunits from different complexes or by indirect interactions through coupling nodes that interact with two or more subunits from different complexes. The dissection of this network facilitates the understanding of a dynamic but elaborate transport machinery in protein/membrane trafficking. The disruption of this network may lead to abnormal trafficking or defective organellar development as described in patients with Hermansky-Pudlak syndrome.
文摘A 10-year-old Chinese boy who had a history of congenital thrombocytopathy presented with severe iron deficiency anemia secondary to chronic gastric inflammation and duodenal ulcerations. Subtle oculocutaneous albinism led to the finding of diminished dense bodies in the platelets under electron microscopy, hence the diagnosis of Hermansky-Pudlak syndrome (HPS). Biopsies from the stomach and duodenum revealed a lymphocytic infiltration in the submucosa, but H pylori infection was absent. The gastroduodenitis responded to the treatment with omeprazole while iron deficiency anemia was corrected by oral iron therapy. HPS is a rare cause of congenital bleeding disorder with multisystemic manifestations. Upper gastrointestinal involvement is rare and should be distinguished from a mere manifestation of the bleeding diathesis.
文摘Hermansky-Pudlak syndrome (HPS) is an autosomal recessive disorder characterized by oculocutaneous albinism(OCA), bleeding tendency, and lysosomal accumulation of ceroid-like material. Seven genetically distinct subtypes of HPS are known in humans; most are rare outside of Puerto Rico. Here, we describe the analysis of the HPS1 gene in 24 Japanese OCA patients who lacked mutations in the four genes known to cause OCA (TYR/OCA1, P/OCA2, TVRP1/OCA3, and MATP/OCA4), and the identification of eight different HPS1 mutations in ten of these patients, four of which were novel (W583X,L668P, 532insC,1691delA).An IVS5 + 5G→ A splice consensus mutation was particularly frequent, the result of a founder effect for this allele in Japanese patients. Functional analysis by transfection of the L668P variant into Hps1-mutant melanep mouse melanocytes showed that this missense substitution is pathologic, resulting in an Hps-1 protein that is unable to assemble into the biogenesis of lysosome-related organelles complex-3.
