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Journal of Osteopathic Medicine Nov 2022
Topics: Humans; Hermanski-Pudlak Syndrome
PubMed: 35670551
DOI: 10.1515/jom-2022-0068 -
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 -
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 -
Platelets May 2020Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder characterized by defective biogenesis of lysosome-related organelles. Clinical manifestations...
Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder characterized by defective biogenesis of lysosome-related organelles. Clinical manifestations include a bleeding diathesis due to a platelet delta storage pool deficiency, oculocutaneous albinism, inflammatory bowel disease, neutropenia, and pulmonary fibrosis. Ten genes associated with HPS are identified to date, and each gene encodes a protein subunit of either Biogenesis of Lysosome-related Organelles Complex (BLOC)-1, BLOC-2, BLOC-3, or the Adaptor Protein-3 complex. Several genetic variants and phenotypic heterogeneities are reported in individuals with HPS, who generally exhibit easy bruisability and increased bleeding. Desmopressin, pro-coagulants, or platelet transfusion may be used as prophylaxis or treatment for excessive bleeding in patients with HPS. However, response to desmopressin can be variable. Platelets are effective in preventing or treating bleeding in individuals with HPS, but platelets should be transfused judiciously to limit alloimmunization in patients with HPS who are at risk of developing pulmonary fibrosis and may be potential candidates for lung transplantation. The discovery of new genes associated with HPS in people with excessive bleeding and hypopigmentation of unknown etiology may be facilitated by the use of next-generation sequencing or panel-based genetic testing.
Topics: Aminocaproic Acid; Antifibrinolytic Agents; Blood Platelets; Carrier Proteins; Contusions; Deamino Arginine Vasopressin; Hemorrhage; Hermanski-Pudlak Syndrome; Humans; Hypopigmentation; Lysosomes; Nerve Tissue Proteins; Proteins; Tranexamic Acid
PubMed: 32436471
DOI: 10.1080/09537104.2019.1663810 -
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 -
Scientific Reports Mar 2020Deletion of dystrobrevin binding protein 1 has been linked to Hermansky-Pudlak syndrome type 7 (HPS-7), a rare disease characterized by oculocutaneous albinism and...
Deletion of dystrobrevin binding protein 1 has been linked to Hermansky-Pudlak syndrome type 7 (HPS-7), a rare disease characterized by oculocutaneous albinism and retinal dysfunction. We studied dysbindin-1 null mutant mice (Dys) to shed light on retinal neurodevelopment defects in HPS-7. We analyzed the expression of a focused set of miRNAs in retina of wild type (WT), Dys and Dys mice. We also investigated the retinal function of these mice through electroretinography (ERG). We found that miR-101-3p, miR-137, miR-186-5p, miR-326, miR-382-5p and miR-876-5p were up-regulated in Dysmice retina. Dys mice showed significant increased b-wave in ERG, compared to WT mice. Bioinformatic analysis highlighted that dysregulated miRNAs target synaptic plasticity and dopaminergic signaling pathways, affecting retinal functions of Dys mice. Overall, the data indicate potential mechanisms in retinal neurodevelopment of Dys mice, which may have translational significance in HSP-7 patients, both in terms of diagnostic/prognostic biomarkers and novel pharmacological targets.
Topics: Animals; Computational Biology; Gene Expression Regulation; Hermanski-Pudlak Syndrome; Mice; Mice, Inbred C57BL; MicroRNAs; Molecular Targeted Therapy; Prognosis; Retina
PubMed: 32132582
DOI: 10.1038/s41598-020-60931-5 -
European Review For Medical and... Nov 2022The incidence of idiopathic pulmonary fibrosis is increasing year by year in the world, which has a greater impact on the quality of life of patients. In the past,... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
The incidence of idiopathic pulmonary fibrosis is increasing year by year in the world, which has a greater impact on the quality of life of patients. In the past, symptomatic treatment was used in clinical practice, but the overall effect is still not good. Multiple clinical studies have demonstrated the efficacy of pirfenidone in the treatment of idiopathic pulmonary fibrosis; however, adverse reactions have been reported. We, therefore, systematically evaluated the effectiveness and safety of pirfenidone in patients with idiopathic pulmonary fibrosis.
PATIENTS AND METHODS
Relevant studies were retrieved from the Embase, PubMed, Web of Science, Cochrane Library, China National Knowledge Infrastructure (CNKI), Chinese Biomedical Literature (CBM), Wanfang and Weipu databases between January 1999 and May 2020, including the keywords "pirfenidone" and "idiopathic pulmonary fibrosis", were included in our systematic review. Review Manager 5.4 software was used for data synthesis, and analyses of publication bias and sensitivity.
RESULTS
Our systematic review included 13 studies involving a total of 13247 patients with idiopathic pulmonary fibrosis. Pirfenidone was associated with reduced declines in vital capacity (VC) and forced vital capacity (FVC) from baseline in patients with hermansky-pudlak syndrome (HPS)-related pulmonary fibrosis and to moderate idiopathic pulmonary fibrosis (IPF). Pirfenidone treatment was associated with lower reductions in FVC, lower reductions in 6-minute walking test distance, lower decreases in minimum oxygen saturation during the 6-minute walking test, lower all-cause death, lower relative risk of IPF-related death and increased progression-free survival compared to placebo. Progression-free survival was significantly longer in the pirfenidone group. The incidence of gastrointestinal, skin, nervous system, and liver function-related adverse events was significantly higher in the pirfenidone group compared to the control group.
CONCLUSIONS
Pirfenidone has efficacy in delaying the progression of idiopathic pulmonary fibrosis. Pirfenidone is well-tolerated by the majority of patients; however, mild adverse reactions related to the gastrointestinal tract, skin, nervous system, and liver function are common. Overall, Pirfenidone may be an effective and well-tolerated treatment option for idiopathic pulmonary fibrosis.
Topics: Humans; Hermanski-Pudlak Syndrome; Quality of Life; Idiopathic Pulmonary Fibrosis; Vital Capacity; Skin
PubMed: 36459024
DOI: 10.26355/eurrev_202211_30377 -
Polish Archives of Internal Medicine Sep 2020
Topics: Albinism; Hermanski-Pudlak Syndrome; Humans; Pulmonary Fibrosis
PubMed: 32495608
DOI: 10.20452/pamw.15418 -
Clinical and Translational Medicine Jul 2021Hermansky-Pudlak syndrome (HPS) is a rare genetic disorder which, in its most common and severe form, HPS-1, leads to fatal adult-onset pulmonary fibrosis (PF) with no...
Hermansky-Pudlak syndrome (HPS) is a rare genetic disorder which, in its most common and severe form, HPS-1, leads to fatal adult-onset pulmonary fibrosis (PF) with no effective treatment. We evaluated the role of the endocannabinoid/CB R system and inducible nitric oxide synthase (iNOS) for dual-target therapeutic strategy using human bronchoalveolar lavage fluid (BALF), lung samples from patients with HPS and controls, HPS-PF patient-derived lung fibroblasts, and bleomycin-induced PF in pale ear mice (HPS1 ). We found overexpression of CB R and iNOS in fibrotic lungs of HPSPF patients and bleomycin-infused pale ear mice. The endocannabinoid anandamide was elevated in BALF and negatively correlated with pulmonary function parameters in HPSPF patients and pale ear mice with bleomycin-induced PF. Simultaneous targeting of CB R and iNOS by MRI-1867 yielded greater antifibrotic efficacy than inhibiting either target alone by attenuating critical pathologic pathways. Moreover, MRI-1867 treatment abrogated bleomycin-induced increases in lung levels of the profibrotic interleukin-11 via iNOS inhibition and reversed mitochondrial dysfunction via CB R inhibition. Dual inhibition of CB R and iNOS is an effective antifibrotic strategy for HPSPF.
Topics: Adult; Animals; Antifibrotic Agents; Arachidonic Acids; Bleomycin; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Endocannabinoids; Female; Fibroblasts; Hermanski-Pudlak Syndrome; Humans; Interleukin-11; Lung; Male; Mice, Inbred C57BL; Middle Aged; Nitric Oxide Synthase Type II; Polyunsaturated Alkamides; Pulmonary Fibrosis; Receptor, Cannabinoid, CB1; Transforming Growth Factor beta1; Mice
PubMed: 34323400
DOI: 10.1002/ctm2.471