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
Hermansky-Pudlak Syndrome (HPS) is a rare genetic condition characterized by platelet function abnormalities and oculocutaneous albinism. Other systemic manifestations of the disease include pulmonary fibrosis, granul...Hermansky-Pudlak Syndrome (HPS) is a rare genetic condition characterized by platelet function abnormalities and oculocutaneous albinism. Other systemic manifestations of the disease include pulmonary fibrosis, granulomatous colitis, impaired renal function, and cardiomyopathy. Due to the systemic extent of the disease, HPS has multiple anesthetic concerns and requires a detailed preoperative evaluation and close perioperative monitoring.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
Oculocutaneous albinism（OCA） is an autosomal recessive disorder characterized by hypopigmentation in eyes,hair and skin,accompanied with vision loss.Currently,six genes have been identified as causative genes for no...Oculocutaneous albinism（OCA） is an autosomal recessive disorder characterized by hypopigmentation in eyes,hair and skin,accompanied with vision loss.Currently,six genes have been identified as causative genes for non-syndromic OCA（OCA-1w4,6,7）,and ten genes for syndromic OCA（HPS-1e9,CHS-1）.Genetic counseling of 51 Chinese OCA families（39 OCA-1 with mutations in the TYR gene,6 OCA-2 with mutations in the OCA2 gene,4 OCA-4 with mutations in the SLC45A2 gene,1 HPS-1（Hermanskye Pudlak syndrome-1） with mutation in the HPS1 gene,and 1 mixed OCA-1 and OCA-4） led us to perform the prenatal genetic testing of OCA using amniotic fluid cells through the implementation of our optimized strategy.In our cohort,eleven previously unidentified alleles（PUAs）（5 in TYR,2 in OCA2,and 4 in SLC45A2） were found.Three missense PUAs（p.C112 R,p.H363 R and p.G379 V of TYR） and one in-frame deletional PUA（p.S222 del of SLC24A5） led to fetuses with OCA when co-inherited with other disease causative alleles.Three PUAs（p.P152 H and p.W272 X of TYR,p.A486 T of SLC24A5） identified in the OCA probands did not co-transmit with known pathological alleles and thus gave rise to unaffected fetuses.Four PUAs（p.Q83 X and p.A658 T of TYR,p.G161 R and p.G366 R of SLC24A5） did not transmit to the unaffected fetuses.In addition,the in vitro transfection assays showed that the p.S192 Y variant of TYR produced less pigment compared to the wild-type allele.A fetus with a digenic carrier of OCA-1 and OCA-4 was unaffected.In combination with functional assays,the family inheritance pattern is useful for the evaluation of pathogenicity of PUAs and genetic counseling of OCA.展开更多
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
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.
文摘Hermansky-Pudlak Syndrome (HPS) is a rare genetic condition characterized by platelet function abnormalities and oculocutaneous albinism. Other systemic manifestations of the disease include pulmonary fibrosis, granulomatous colitis, impaired renal function, and cardiomyopathy. Due to the systemic extent of the disease, HPS has multiple anesthetic concerns and requires a detailed preoperative evaluation and close perioperative monitoring.
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.
基金partially supported by grants from the National Natural Science Foundation of China(Nos.81472871 and31230046)the Natural Science Foundation of Beijing(No.7132073)the State Key Laboratory of Molecular Developmental Biology of China(No.2013-MDB-KF-03)
文摘Oculocutaneous albinism（OCA） is an autosomal recessive disorder characterized by hypopigmentation in eyes,hair and skin,accompanied with vision loss.Currently,six genes have been identified as causative genes for non-syndromic OCA（OCA-1w4,6,7）,and ten genes for syndromic OCA（HPS-1e9,CHS-1）.Genetic counseling of 51 Chinese OCA families（39 OCA-1 with mutations in the TYR gene,6 OCA-2 with mutations in the OCA2 gene,4 OCA-4 with mutations in the SLC45A2 gene,1 HPS-1（Hermanskye Pudlak syndrome-1） with mutation in the HPS1 gene,and 1 mixed OCA-1 and OCA-4） led us to perform the prenatal genetic testing of OCA using amniotic fluid cells through the implementation of our optimized strategy.In our cohort,eleven previously unidentified alleles（PUAs）（5 in TYR,2 in OCA2,and 4 in SLC45A2） were found.Three missense PUAs（p.C112 R,p.H363 R and p.G379 V of TYR） and one in-frame deletional PUA（p.S222 del of SLC24A5） led to fetuses with OCA when co-inherited with other disease causative alleles.Three PUAs（p.P152 H and p.W272 X of TYR,p.A486 T of SLC24A5） identified in the OCA probands did not co-transmit with known pathological alleles and thus gave rise to unaffected fetuses.Four PUAs（p.Q83 X and p.A658 T of TYR,p.G161 R and p.G366 R of SLC24A5） did not transmit to the unaffected fetuses.In addition,the in vitro transfection assays showed that the p.S192 Y variant of TYR produced less pigment compared to the wild-type allele.A fetus with a digenic carrier of OCA-1 and OCA-4 was unaffected.In combination with functional assays,the family inheritance pattern is useful for the evaluation of pathogenicity of PUAs and genetic counseling of OCA.
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.
