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
57 Reads
  • 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.
    BMC Genomics 06/2014; 15(1):533. DOI:10.1186/1471-2164-15-533 · 3.99 Impact Factor
  • 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.
    BMC Psychiatry 10/2013; 13(1):276. DOI:10.1186/1471-244X-13-276 · 2.21 Impact Factor
  • Source
    • "HPS2 belongs to a genetically heterogenous group of autosomal recessive disorders that share oculocutaneous albinism and platelet storage disease. In humans, nine causative genes have been cloned and sequenced: each defective gene is involved in formation, transport or fusion of intracellular vesicles of lysosomal lineage [47]. Type 2 represents the HPS type that was first associated to immunodeficiency, specifically neutropenia. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Hypopigmentation disorders that are associated with immunodeficiency feature both partial albinism of hair, skin and eyes together with leukocyte defects. These disorders include Chediak Higashi (CHS), Griscelli (GS), Hermansky-Pudlak (HPS) and MAPBP-interacting protein deficiency syndromes. These are heterogeneous autosomal recessive conditions in which the causal genes encode proteins with specific roles in the biogenesis, function and trafficking of secretory lysosomes. In certain specialized cells, these organelles serve as a storage compartment. Impaired secretion of specific effector proteins from that intracellular compartment affects biological activities. In particular, these intracellular granules are essential constituents of melanocytes, platelets, granulocytes, cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. Thus, abnormalities affect pigmentation, primary hemostasis, blood cell counts and lymphocyte cytotoxic activity against microbial pathogens. Among eight genetically distinct types of HPS, only type 2 is characterized by immunodeficiency. Recently, a new subtype, HPS9, was defined in patients presenting with immunodeficiency and oculocutaneous albinism, associated with mutations in the pallidin-encoding gene, PLDN. Hypopigmentation together with recurrent childhood bacterial or viral infections suggests syndromic albinism. T and NK cell cytotoxicity are generally impaired in patients with these disorders. Specific clinical and biochemical phenotypes can allow differential diagnoses among these disorders before molecular testing. Ocular symptoms, including nystagmus, that are usually evident at birth, are common in patients with HPS2 or CHS. Albinism with short stature is unique to MAPBP-interacting protein (MAPBPIP) deficiency, while hemophagocytic lymphohistiocytosis (HLH) mainly suggests a diagnosis of CHS or GS type 2 (GS2). Neurological disease is a long-term complication of CHS, but is uncommon in other syndromic albinism. Chronic neutropenia is a feature of HPS2 and MAPBPIP-deficiency syndrome, whereas it is usually transient in CHS and GS2. In every patient, an accurate diagnosis is required for prompt and appropriate treatment, particularly in patients who develop HLH or in whom bone marrow transplant is required. This review describes the molecular and pathogenetic mechanisms of these diseases, focusing on clinical and biochemical aspects that allow early differential diagnosis.
    Orphanet Journal of Rare Diseases 10/2013; 8(1):168. DOI:10.1186/1750-1172-8-168 · 3.36 Impact Factor
Show more