Wei, M. L. Hermansky-Pudlak syndrome: a disease of protein trafficking and organelle function. Pigment Cell Res. 19, 19-42

Department of Dermatology, Veterans Affairs Medical Center 190, University of California, 4150 Clement St., San Francisco, USA.
Pigment Cell Research (Impact Factor: 4.29). 03/2006; 19(1):19-42. DOI: 10.1111/j.1600-0749.2005.00289.x
Source: PubMed


The Hermansky-Pudlak syndrome (HPS) is a collection of related autosomal recessive disorders which are genetically heterogeneous. There are eight human HPS subtypes, characterized by oculocutaneous albinism and platelet storage disease; prolonged bleeding, congenital neutropenia, pulmonary fibrosis, and granulomatous colitis can also occur. HPS is caused primarily by defects in intracellular protein trafficking that result in the dysfunction of intracellular organelles known as lysosome-related organelles. HPS gene products are all ubiquitously expressed and all associate in various multi-protein complexes, yet HPS has cell type-specific disease expression. Impairment of specialized secretory cells such as melanocytes, platelets, lung alveolar type II epithelial cells and cytotoxic T cells are observed in HPS. This review summarizes recent molecular, biochemical and cell biological analyses together with clinical studies that have led to the correlation of molecular pathology with clinical manifestations and led to insights into such diverse disease processes such as albinism, fibrosis, hemorrhage, and congenital neutropenia.

Download full-text


Available from: Maria L Wei, Jan 07, 2015
  • Source
    • "Rab38 and the closely related Rab32 work redundantly in melanocytes, as demonstrated by depletion of Rab32 in in vitro cultured cht epidermal melanocytes, which severely impairs the transport of Tyr and Tyrp1 to melanosomes, resulting in severe hypopigmentation[12]. Mouse Rab32 and Rab38 are paralogues, sharing 67 % amino acid identity and are considered to have originated from the vertebrate whole genome duplication (WGD) that occurred before the Gnathostomata radiation171819. Furthermore, it has been shown that the Rab38 gene is mutated in ruby rats[20], a strain characterized by hypopigmentation and platelet storage pool deficiency related to Hermansky-Pudlak syndrome (HPS)[21]. This pathology in humans causes oculocutaneous albinism, easy bleedings, abnormal lysosomal ceroid lipofuscin and pulmonary fibrosis in 40–50 years-old patients[22]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The regulation of cellular membrane trafficking in all eukaryotes is a very complex mechanism, mostly regulated by the Rab family proteins. Among all membrane-enclosed organelles, melanosomes are the cellular site for synthesis, storage and transport of melanin granules, making them an excellent model for studies on organelle biogenesis and motility. Specific Rab proteins, as Rab32 and Rab38, have been shown to play a key role in melanosome biogenesis. We analysed the Rab32 and Rab38 genes in the teleost zebrafish and in the cephalochordate amphioxus, gaining insight on their evolutionary history following gene and genome duplications. We studied the molecular evolution of Rab supergroup III in deuterostomes by phylogenetic reconstruction, intron and synteny conservation. We discovered a novel amino acid stretch, named FALK, shared by three related classes belonging to Rab supergroup III: Rab7L1, Rab32LO and Rab32/Rab38. Among these, we demonstrated that the Rab32LO class, already present in the last common eukaryotic ancestor, was lost in urochordates and vertebrates. Synteny shows that one zebrafish gene, Rab38a, which is expressed in pigmented cells, retained the linkage with tyrosinase, a protein essential for pigmentation. Moreover, the chromosomal linkage of Rab32 or Rab38 with a member of the glutamate receptor metabotropic (Grm) family has been retained in all analysed gnathostomes, suggesting a conserved microsynteny in the vertebrate ancestor. Expression patterns of Rab32 and Rab38 genes in zebrafish, and Rab32/38 in amphioxus, indicate their involvement in development of pigmented cells and notochord. Phylogenetic, intron conservation and synteny analyses point towards an evolutionary scenario based on a duplication of a single invertebrate Rab32/38 gene giving rise to vertebrate Rab32 and Rab38. The expression patterns of Rab38 paralogues highlight sub-functionalization event. Finally, the discovery of a chromosomal linkage between the Rab32 or Rab38 gene with a Grm opens new perspectives on possible conserved bystander gene regulation across the vertebrate evolution.
    Preview · Article · Dec 2016 · BMC Evolutionary Biology
  • Source
    • "LPS-induced regulation of HPS5 is quite intriguing. HPS5 (Ruby eye-2) is an ubiquitously expressed protein [71] in vivo related to melanocyte differentiation and eumelanin synthesis [60]. Its absence influences the distribution of CD63 [72], the platelet activation antigen essential for leukocyte recruitment [73]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Immunoecology aims to explain variation among hosts in the strength and efficacy of immunological defences in natural populations. This requires development of biomarkers of the activation of the immune system so that they can be collected non-lethally and sampled from small amounts of easily obtainable tissue. We used transcriptome profiling in wild greenfinches (Carduelis chloris) to detect whole blood transcripts that most profoundly indicate upregulation of antimicrobial defences during acute phase response. The more general aim of this study was to obtain a functional annotation of a substantial portion of the greenfinch transcriptome that would enable to gain access to more specific genomic tools in subsequent studies. The birds received either bacterial lipopolysaccharide or saline injections and RNA-seq transcriptional profiling was performed 12 h after treatment to provide initial functional annotation of the transcriptome and assess whole blood response to immune stimulation. Results A total of 66,084 transcripts were obtained from de novo Trinty assembly, out of which 23,153 could be functionally annotated. Only 1,911 of these were significantly upregulated or downregulated. The manipulation caused marked upregulation of several transcripts related to immune activation. These included avian-specific antimicrobial agents avidin and gallinacin, but also some more general host response genes, such as serum amyloid A protein, lymphocyte antigen 75 and copper-transporting ATPase 1. However, links with avian immunity for most differentially regulated transcripts remained rather hypothetical, as a large set of differentially expressed transcripts lacked functional annotation. Conclusions This appears to be the first large scale transcriptional profiling of immune function in passerine birds. The transcriptomic data obtained suggest novel markers for the assessment of the immunological state of wild passerines. Characterizing the function of those possible novel infection markers would assist future vertebrate genome annotation. The extensive sequence information collected enables to identify possible target and housekeeping genes needed to gain access to more specific genomic tools in future studies. Electronic supplementary material The online version of this article (doi:10.1186/1471-2164-15-533) contains supplementary material, which is available to authorized users.
    Full-text · Article · Jun 2014 · BMC Genomics
  • Source
    • "HPS is caused by a mutation in one of the genes named HPS1 to HPS9, which encode subunit proteins that consist of multiprotein complexes, the adaptor protein complex-3 (AP-3), and the biogenesis of lysosome-related organelles complex (BLOC)-1, 2, and 3 [18,19]. BLOC-1, BLOC-2, and AP-3 interact to play a pivotal role in sorting and trafficking membrane proteins on early endosomes [20-24]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The Hermansky--Pudlak Syndrome Type 4 (HPS4) gene, which encodes a subunit protein of the biogenesis of lysosome-related organelles complex (BLOC)-3, which is involved in late endosomal trafficking, is associated with schizophrenia; however, its clinical relevance in schizophrenia remains unknown. The purpose of the present study was to investigate whether HPS4 is associated with cognitive functions in patients with schizophrenia and healthy controls and with the clinical profiles of patients with schizophrenia. We investigated the association of variants of HPS4 with clinical symptoms and cognitive function in Japanese patients with schizophrenia (n = 240) and age-matched healthy control subjects (n = 240) with single nucleotide polymorphisms (SNP)- or haplotype-based linear regression. We analyzed five tagging SNPs (rs4822724, rs61276843, rs9608491, rs713998, and rs2014410) of HPS4 and 2--5 locus haplotypes of these five SNPs. The cognitive functions of patients and healthy subjects were evaluated with the Brief Assessment of Cognition in Schizophrenia, Japanese-language version, and the patients were assessed for their symptomatology with the Positive and Negative Symptom Scale (PANSS). In patients with schizophrenia, rs713998 was significantly associated with executive function under the dominant genetic model (P = 0.0073). In healthy subjects, there was a significant association between working memory and two individual SNPs under the recessive model (rs9608491: P = 0.001; rs713998: P = 0.0065) and two haplotypes (rs9608491-713998: P = 0.0025; rs61276843-9608491-713998: P = 0.0064). No significant association was found between HPS4 SNPs and PANSS scores or premorbid IQ, as measured by the Japanese version of the National Adult Reading Test. These findings suggested the involvement of HPS4 in the working memory of healthy subjects and in the executive function deficits in schizophrenia.
    Full-text · Article · Oct 2013 · BMC Psychiatry
Show more