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Journal of Osteopathic Medicine Nov 2022
Topics: Humans; Hermanski-Pudlak Syndrome
PubMed: 35670551
DOI: 10.1515/jom-2022-0068 -
Clinics in Chest Medicine Sep 2016Hermansky-Pudlak syndrome (HPS) is an autosomal recessive disorder that is associated with oculocutaneous albinism, bleeding diatheses, granulomatous colitis, and highly... (Review)
Review
Hermansky-Pudlak syndrome (HPS) is an autosomal recessive disorder that is associated with oculocutaneous albinism, bleeding diatheses, granulomatous colitis, and highly penetrant pulmonary fibrosis in some subtypes, including HPS-1, HPS-2, and HPS-4. HPS pulmonary fibrosis shows many of the clinical, radiologic, and histologic features found in idiopathic pulmonary fibrosis, but occurs at a younger age. Despite knowledge of the underlying genetic defects, there are currently no definitive therapeutic or preventive approaches for HPS pulmonary fibrosis other than lung transplant.
Topics: Albinism; Albinism, Oculocutaneous; Arteriovenous Malformations; Blood Coagulation Disorders; Crohn Disease; Epistaxis; Gastrointestinal Diseases; Hemorrhagic Disorders; Hermanski-Pudlak Syndrome; Humans; Hypertension, Pulmonary; Intracranial Arteriovenous Malformations; Liver Diseases; Pulmonary Artery; Pulmonary Fibrosis; Pulmonary Veins; Telangiectasis
PubMed: 27514596
DOI: 10.1016/j.ccm.2016.04.012 -
Human Mutation Mar 2020Hermansky-Pudlak syndrome (HPS) is a group of 10 autosomal recessive multisystem disorders, each defined by the deficiency of a specific gene. HPS-associated genes...
Hermansky-Pudlak syndrome (HPS) is a group of 10 autosomal recessive multisystem disorders, each defined by the deficiency of a specific gene. HPS-associated genes encode components of four ubiquitously expressed protein complexes: Adaptor protein-3 (AP-3) and biogenesis of lysosome-related organelles complex-1 (BLOC-1) through -3. All individuals with HPS exhibit albinism and a bleeding diathesis; additional features occur depending on the defective protein complex. Pulmonary fibrosis is associated with AP-3 and BLOC-3 deficiency, immunodeficiency with AP-3 defects, and gastrointestinal symptoms are more prevalent and severe in BLOC-3 deficiency. Therefore, identification of the HPS subtype is valuable for prognosis, clinical management, and treatment options. The prevalence of HPS is estimated at 1-9 per 1,000,000. Here we summarize 264 reported and novel variants in 10 HPS genes and estimate that ~333 Puerto Rican HPS subjects and ~385 with other ethnicities are reported to date. We provide pathogenicity predictions for missense and splice site variants and list variants with high minor allele frequencies. Current cellular and clinical aspects of HPS are also summarized. This review can serve as a manifest for molecular diagnostics and genetic counseling aspects of HPS.
Topics: Alleles; Genetic Association Studies; Genetic Predisposition to Disease; Hermanski-Pudlak Syndrome; Humans; Intracellular Signaling Peptides and Proteins; Membrane Proteins; Multigene Family; Mutation; Phenotype
PubMed: 31898847
DOI: 10.1002/humu.23968 -
Mucosal Immunology Jun 2022Hermansky-Pudlak syndrome (HPS) types 1 and 4 are caused by defective vesicle trafficking. The mechanism for Crohn's disease-like inflammation, lung fibrosis, and...
Hermansky-Pudlak syndrome (HPS) types 1 and 4 are caused by defective vesicle trafficking. The mechanism for Crohn's disease-like inflammation, lung fibrosis, and macrophage lipid accumulation in these patients remains enigmatic. The aim of this study is to understand the cellular basis of inflammation in HPS-1. We performed mass cytometry, proteomic and transcriptomic analyses to investigate peripheral blood cells and serum of HPS-1 patients. Using spatial transcriptomics, granuloma-associated signatures in the tissue of an HPS-1 patient with granulomatous colitis were dissected. In vitro studies were conducted to investigate anti-microbial responses of HPS-1 patient macrophages and cell lines. Monocytes of HPS-1 patients exhibit an inflammatory phenotype associated with dysregulated TNF, IL-1α, OSM in serum, and monocyte-derived macrophages. Inflammatory macrophages accumulate in the intestine and granuloma-associated macrophages in HPS-1 show transcriptional signatures suggestive of a lipid storage and metabolic defect. We show that HPS1 deficiency leads to an altered metabolic program and Rab32-dependent amplified mTOR signaling, facilitated by the accumulation of mTOR on lysosomes. This pathogenic mechanism translates into aberrant bacterial clearance, which can be rescued with mTORC1 inhibition. Rab32-mediated mTOR signaling acts as an immuno-metabolic checkpoint, adding to the evidence that defective bioenergetics can drive hampered anti-microbial activity and contribute to inflammation.
Topics: Humans; Hermanski-Pudlak Syndrome; Proteomics; Inflammation; TOR Serine-Threonine Kinases; Lipids
PubMed: 36302964
DOI: 10.1038/s41385-022-00572-1 -
Orphanet Journal of Rare Diseases Jul 2022The Hermansky-Pudlak syndrome (HPS) is a genetically heterogeneous group of diseases characterized by oculocutaneous albinism, bleeding diathesis, and systemic...
BACKGROUND
The Hermansky-Pudlak syndrome (HPS) is a genetically heterogeneous group of diseases characterized by oculocutaneous albinism, bleeding diathesis, and systemic complications. It is the most common genetic disorder in Puerto Rico. These patients are at a significant risk of developing a variety of skin complications and little is known about the prevalence of dermatologic diagnoses in this population.
OBJECTIVES
To report dermatologic manifestations in patients with Hermansky-Pudlak syndrome (HPS). Secondary aims include skin concerns, sun protection habits, barriers to dermatologic care, and skin cancer knowledge.
METHODS
Cross-sectional study with twenty-nine Puerto Rican patients who carried a clinical diagnosis of HPS type 1 or type 3 through a telephonic questionnaire.
RESULTS
Twenty-nine patients participated with a mean (SD) age of 37.3 (16.8) years and the majority were female (69%). The most common diagnoses were skin cancer (34.5%), acne (34.5%), bacterial skin infections (34.5%), warts (24%), urticaria (17.2%), and psoriasis (17.2%). The most common skin concerns were dry skin (62.1%), hair loss (58.9%), redness (34.5%), moles (31%), and rash (31%). The most common sun protection behavior was wearing a shirt that covers the shoulders (93.1%, often or always) and the least common was wearing a hat (24.1%, often or always). Higher income was significantly associated with being more likely to use sunscreen often or always (OR = 3.38, 95% CI 1.02-11.18, p = 0.04). Those in northern urban areas were significantly less likely to report barriers to dermatologic care (OR = 0.13, 95% CI 0.02-0.76, p = 0.02).
CONCLUSIONS
This study provides an important overview of the most common self-reported skin manifestations in patients with HPS. Unfortunately, a high prevalence of cutaneous malignancy was reported. The results stress the need for adequate care and potential interventions to promote sun protection behaviors and skin cancer prevention.
Topics: Adult; Albinism; Cross-Sectional Studies; Female; Hemorrhagic Disorders; Hermanski-Pudlak Syndrome; Humans; Male; Skin Neoplasms
PubMed: 35907869
DOI: 10.1186/s13023-022-02464-w -
Genes Jul 2022Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive syndromic form of albinism, characterized by oculocutaneous albinism (OCA) and other systemic...
Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive syndromic form of albinism, characterized by oculocutaneous albinism (OCA) and other systemic complications. The purpose of this study was to investigate patients with HPS-associated gene mutations and describe associated ocular and extraocular phenotypes. Fifty-four probands clinically diagnosed as albinism were enrolled. Ophthalmic examinations and genetic testing were performed in all subjects. The phenotypic and genetic features were evaluated. HPS-associated gene mutation was identified in four of the patients with albinism phenotype. Clinically, photophobia, and nystagmus was detected in all (4/4) patients, and strabismus was found in one (1/4) patient. Fundus examination revealed fundus hypopigmentation and foveal hypoplasia in all (8/8) eyes. Eight novel causative mutations were detected in these four HPS probands. Five (62.5%, 5/8) of the mutations were nonsense, two of the mutations were missense (25%, 2/8), and one of the mutations was frameshift (12.5%, 1/8). All patients in our study carried compound heterozygous variants, and all these pathogenic variants were identified to be novel, with most (62.5%, 5/8) of the mutations being nonsense. Our results improved the understanding of clinical ocular features, and expanded the spectrum of known variants and the genetic background of HPS.
Topics: Eye; Genetic Testing; Hermanski-Pudlak Syndrome; Humans; Mutation; Phenotype
PubMed: 35886065
DOI: 10.3390/genes13071283 -
Annals of the American Thoracic Society Oct 2016Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive genetic disorder characterized by oculocutaneous albinism and a bleeding diathesis due to platelet... (Review)
Review
Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive genetic disorder characterized by oculocutaneous albinism and a bleeding diathesis due to platelet dysfunction. More than 50% of cases worldwide are diagnosed on the Caribbean island of Puerto Rico. Genetic testing plays a growing role in diagnosis; however, not all patients with HPS have identified genetic mutations. In Puerto Rico, patients with HPS are often identified shortly after birth by their albinism, although the degree of hypopigmentation is highly variable. Ten subtypes have been described. Patients with HPS-1, HPS-2, and HPS-4 tend to develop pulmonary fibrosis in Puerto Rico; 100% of patients with HPS-1 develop HPS-PF. HPS-PF and idiopathic pulmonary fibrosis are considered similar entities (albeit with distinct causes) because both can show similar histological disease patterns. However, in contrast to idiopathic pulmonary fibrosis, HPS-PF manifests much earlier, often at 30-40 years of age. The progression of HPS-PF is characterized by the development of dyspnea and increasingly debilitating hypoxemia. No therapeutic interventions are currently approved by the U.S. Food and Drug Administration for the treatment of HPS and HPS-PF. However, the approval of two new antifibrotic drugs, pirfenidone and nintedanib, has prompted new interest in identifying drugs capable of reversing or halting the progression of HPS-PF. Thus, lung transplantation remains the only potentially life-prolonging treatment. At present, two clinical trials are recruiting patients with HPS-PF to identify biomarkers for disease progression. Advances in the diagnosis and management of these patients will require the establishment of multidisciplinary centers of excellence staffed by experts in this disease.
Topics: Animals; Biomarkers; Disease Progression; Hermanski-Pudlak Syndrome; Hispanic or Latino; Humans; Indoles; Lung Transplantation; Membrane Proteins; Mice; Mutation; Puerto Rico; Pulmonary Fibrosis; Pyridones; Randomized Controlled Trials as Topic; Tomography, X-Ray Computed
PubMed: 27529121
DOI: 10.1513/AnnalsATS.201603-186FR -
International Journal of Molecular... Jul 2018is highly expressed in alveolar type II cells, melanocytes, and platelets. These cells are specifically-differentiated cells and contain characteristic intracellular... (Review)
Review
is highly expressed in alveolar type II cells, melanocytes, and platelets. These cells are specifically-differentiated cells and contain characteristic intracellular organelles called lysosome-related organelles, i.e., lamellar bodies in alveolar type II cells, melanosomes in melanocytes, and dense granules in platelets. There are -mutant rodents, i.e., mice and rats. While mice only show oculocutaneous albinism, rats show oculocutaneous albinism and prolonged bleeding time and, hence, are a rat model of Hermansky-Pudlak syndrome (HPS). Most patients with HPS suffer from fatal interstitial pneumonia by middle age. The lungs of both mice and rats show remarkably increased amounts of lung surfactant and conspicuously enlarged lysosome-related organelles, i.e., lamellar bodies, which are also characteristic of the lungs in human HPS. There are 16 mutant HPS-mouse strains, of which ten mutant genes have been identified to be causative in patients with HPS thus far. The gene products of eight of the ten genes constitute one of the three protein complexes, i.e., biogenesis of lysosome-related organelle complex-1, -2, -3 (BLOC-1, -2, -3). Patients with HPS of the mutant BLOC-3 genotype develop interstitial pneumonia. Recently, BLOC-3 has been elucidated to be a guanine nucleotide exchange factor for Rab38. Growing evidence suggests that is an additional candidate gene of human HPS that displays the lung phenotype.
Topics: Animals; Carrier Proteins; Disease Models, Animal; Guanine Nucleotide Exchange Factors; Hermanski-Pudlak Syndrome; Humans; Lung; Lung Diseases, Interstitial; Mice; Nerve Tissue Proteins; Proteins; Pulmonary Surfactants; Rats; rab GTP-Binding Proteins
PubMed: 30060521
DOI: 10.3390/ijms19082203 -
Bioscience Reports Oct 2018Platelets respond to vascular injury via surface receptor stimulation and signaling events to trigger aggregation, procoagulant activation, and granule secretion during... (Review)
Review
Platelets respond to vascular injury via surface receptor stimulation and signaling events to trigger aggregation, procoagulant activation, and granule secretion during hemostasis, thrombosis, and vascular remodeling. Platelets contain three major types of secretory granules including dense granules (or δ-granules, DGs), α-granules (AGs), and lysosomes. The contents of platelet granules are specific. Platelet DGs store polyphosphate and small molecules such as ADP, ATP, Ca, and serotonin, while AGs package most of the proteins that platelets release. The platelet DGs and AGs are regarded as being budded from the endosomes and the -Golgi network (TGN), respectively, and then matured from multivesicular bodies (MVBs). However, the sorting machineries between DGs and AGs are different. Inherited platelet disorders are associated with deficiency of DGs and AGs, leading to bleeding diathesis in patients with Hermansky-Pudlak syndrome (HPS), gray platelet syndrome (GPS), and arthrogryposis, renal dysfunction, and cholestasis syndrome (ARC). Here, we reviewed the current understanding about how DGs differ from AGs in structure, biogenesis, and function. In particular, we focus on the sorting machineries that are involved in the formation of these two types of granules to provide insights into their diverse biological functions.
Topics: Arthrogryposis; Blood Platelets; Cholestasis; Cytoplasmic Granules; Endosomes; Gray Platelet Syndrome; Hermanski-Pudlak Syndrome; Humans; Lysosomes; Multivesicular Bodies; Renal Insufficiency; Secretory Vesicles; trans-Golgi Network
PubMed: 30104399
DOI: 10.1042/BSR20180458 -
Traffic (Copenhagen, Denmark) Jun 2019Lysosome-related organelles (LROs) comprise a diverse group of cell type-specific, membrane-bound subcellular organelles that derive at least in part from the... (Review)
Review
Lysosome-related organelles (LROs) comprise a diverse group of cell type-specific, membrane-bound subcellular organelles that derive at least in part from the endolysosomal system but that have unique contents, morphologies and functions to support specific physiological roles. They include: melanosomes that provide pigment to our eyes and skin; alpha and dense granules in platelets, and lytic granules in cytotoxic T cells and natural killer cells, which release effectors to regulate hemostasis and immunity; and distinct classes of lamellar bodies in lung epithelial cells and keratinocytes that support lung plasticity and skin lubrication. The formation, maturation and/or secretion of subsets of LROs are dysfunctional or entirely absent in a number of hereditary syndromic disorders, including in particular the Hermansky-Pudlak syndromes. This review provides a comprehensive overview of LROs in humans and model organisms and presents our current understanding of how the products of genes that are defective in heritable diseases impact their formation, motility and ultimate secretion.
Topics: Animals; Hermanski-Pudlak Syndrome; Humans; Lysosomes; Melanosomes; Weibel-Palade Bodies
PubMed: 30945407
DOI: 10.1111/tra.12646