Disease relevance of HPS1

• Hermansky-Pudlak syndrome (HPS), consisting of oculocutaneous albinism and a bleeding diathesis due to the absence of platelet dense granules, displays extensive locus heterogeneity [1].
• All eight patients have mild symptoms of HPS; two Jewish patients had received the diagnosis of ocular, rather than oculocutaneous, albinism [1].
• Hermansky-Pudlak syndrome type 3 in Ashkenazi Jews and other non-Puerto Rican patients with hypopigmentation and platelet storage-pool deficiency [1].
• Clinically, our HPS-4 patients exhibited iris transillumination, variable hair and skin pigmentation, absent platelet dense bodies, and occasional pulmonary fibrosis and granulomatous colitis, a severe phenotype similar to that of patients with HPS-1 [2].
• In contrast, all four known HPS-causing genes have homologs in mice, a species with 14 different models of HPS, i.e. hypopigmentation and a platelet storage pool deficiency [3].

Psychiatry related information on HPS1

• A neuropsychological test battery was administered immediately following their acute hospitalization and at 1 year postrecovery from HPS [4].
• These results support the construct validity of the two social perception measures, the TRAC-D, and the HPS, as measures of rape proclivity [5].
• Acrofacial dysostosis with growth and mental retardation in three males, one with simultaneous Hermansky-Pudlak syndrome [6].

High impact information on HPS1

• Hermansky-Pudlak syndrome (HPS) is a genetically heterogeneous disease involving abnormalities of melanosomes, platelet dense granules and lysosomes [7].
• Hermansky-Pudlak syndrome is caused by mutations in HPS4, the human homolog of the mouse light-ear gene [8].
• In the mouse, more than 15 loci manifest mutant phenotypes similar to human HPS, including pale ear (ep), the mouse homolog of HPS1 (refs 13,14) [8].
• ADTB3A encodes a coat protein involved in vesicle formation, implicating HPS as a disorder of membrane trafficking [9].
• Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder characterized by oculocutaneous albinism and a storage pool deficiency due to an absence of platelet dense bodies [9].

Chemical compound and disease context of HPS1

• The Hermansky-Pudlak syndrome consists of tyrosine-positive albinism, a defect in the second phase of platelet aggregation, and widespread accumulation of a ceroidlike pigment in tissue [10].
• The effects of intravenous procainamide infusion of 10--14 mg/kg body weight (i.e., 750 mg) of procainamide (PA) on reentry within the His-Purkinje system (HPS) were studied in 13 patients using His bundle electrograms and ventricular extrastimulus method [11].
• Intravenous ribavirin was provided non-selectively for investigational open-label use among persons with suspected hantavirus pulmonary syndrome (HPS) in the United States between 4 June 1993 and 1 September 1994 [12].
• Further, a mouse-human hybrid beta3 integrin-specific Fab fragment, c7E3 (ReoPro), also inhibited the infectivity of HTN, SEO, and PUU as well as HPS-associated hantaviruses, Sin Nombre (SN) and New York-1 (NY-1) [13].
• After the 1993 HPS outbreak in the southwestern United States, the Centers for Disease Control and Prevention initiated long-term studies of the temporal dynamics of hantavirus infection in host populations [14].

Biological context of HPS1

• Taken together, these observations suggest that HPS1 and HPS4 are components of a protein complex that regulates the intracellular localization of lysosomes and late endosomes and may function in a BLOC-1-dependent pathway for melanosome biogenesis [15].
• The coat-color phenotype of young homozygous double-mutant mice deficient in subunits of BLOC-3 (HPS1) and BLOC-1 (pallidin) was indistinguishable from that of BLOC-1 single mutants [15].
• Four novel mutations were discovered, including the first HPS1 missense mutation, 922T>C, in exon 8 [16].
• However, the level of suppression, as well as extent to which up-regulation by isobutylmethylxanthine and cholera toxin was muted, was less that in HPS-1 melanocytes [17].
• To characterize further the recently identified HPS-4 disease on molecular and clinical grounds, we first identified the genomic organization of HPS4, located on chromosome 22q11.2-q12.2, including its intron/exon boundaries [2].

Anatomical context of HPS1

• Sedimentation-velocity and coimmunoprecipitation experiments revealed that HPS4 but not HPS3 associates with HPS1 in a complex, which we term biogenesis of lysosome-related organelles complex 3 (BLOC-3) [15].
• Mutant fibroblasts deficient in either HPS1 or HPS4 displayed abnormal localization of lysosomes and late endosomes, which were less concentrated at the juxtanuclear region in mutant cells than in control fibroblasts [15].
• In the cytosol, HPS1 (but not HPS4) is part of yet another complex, termed BLOC-5 [18].
• In normal human melanocytes, the HPS1 protein was expressed as an approximately 80 kDa molecule with both granular and reticular intracellular profiles [19].
• Hermansky-Pudlak Syndrome (HPS) is a genetically heterogeneous disorder in which mutations in one of several genes interrupts biogenesis of melanosomes, platelet dense bodies, and lysosomes [19].

Associations of HPS1 with chemical compounds

• Melanocytes in the basal epithelial layer of skin from patients with different mutations in the HPS1 gene exhibited occasional large complexes containing dihydroxyphenylalanine-positive cisterna and 50 nm vesicles [20].
• A 1-bp duplication of adenine at codon 441 was found in the HPS gene, namely HPS1, which caused a frameshift [21].
• We performed mutation screening of patients with HPS and failed to identify any CNO defects [22].
• Using indirect immunofluorescence, an increase in co-localization of misrouted tyrosinase with cathepsin-L, a lysosomal cysteine protease, occurred in HPS-1 melanocytes [23].
• The effects of adenosine on the human His-Purkinje system (HPS) were studied in nine patients with complete atrioventricular (AV) block [24].

Physical interactions of HPS1

• Nonsense mutations in ADTB3A cause complete deficiency of the beta3A subunit of adaptor complex-3 and severe Hermansky-Pudlak syndrome type 2 [25].
• This link establishes the evolutionary conservation of a protein complex (HPS-1/HPS-4) that functions similarly to Mon1/Ccz1 in vesicle trafficking to lysosome-related organelles of diverse eukaryotic species [26].

Regulatory relationships of HPS1

• The levels and expression of the proteins CD63 and granulophysin in platelets from control and from a Hermansky-Pudlak syndrome subject (a condition characterized by dense granule and lysosomal deficiencies and the accumulation of ceroid-like material in reticuloendothelial cells) were examined [27].
• Immunological techniques were used to examine the localization of LAMP-2 in control platelets and those from an individual with Hermansky-Pudlak syndrome (HPS), a condition characterised by platelet dense granule deficiency [28].

Other interactions of HPS1

• A third HPS-causing gene, HPS3, was recently identified on the basis of homozygosity mapping of a genetic isolate of HPS in central Puerto Rico [1].
• Within BLOC-3, HPS1 and HPS4 are components of a discrete approximately 200-kDa module termed BLOC-4 [18].
• Each of these HPS subtypes has a murine counterpart, specifically pale ear for HPS-1 and pearl for HPS-2 [29].
• The HPS-6 phenotype in the studied family is unique since it resembles OCA and not HPS [30].
• Melanocyte-specific proteins are aberrantly trafficked in melanocytes of Hermansky-Pudlak syndrome-type 3 [17].

Analytical, diagnostic and therapeutic context of HPS1

• Co-immunoprecipitation experiments demonstrated that epitope-tagged and endogenous HPS1 and HPS4 proteins assemble with each other in vivo [31].
• Size exclusion chromatography and sedimentation velocity analyses of the cytosolic fraction indicate that HPS1 and HPS4 form a moderately asymmetric protein complex with a molecular mass of approximately 175 kDa [31].
• Expression of the 79 kDa HPS1 protein (in M-188 and S-188 cells) or lack of expression (in A-188 cells) was confirmed by Western blotting using two HPS1-protein-specific polyclonal antibodies [20].
• Electron microscopy of a pinkish papule corresponding to the melanocytic nevus revealed markedly aberrant, immature melanosomes, large membranous structures, and giant melanosomes in the vicinity of trans-Golgi network, the characteristic abnormalities because of protein trafficking defects in HPS1 [32].
• We used a real-time quantitative PCR (qPCR) approach to investigate six HPS-1 patients, previously assigned as having homozygous mutations in the HPS1 gene [33].

References