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Hermansky-Pudlak syndrome: Mutation update.

ABSTRACT: 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.

SUBMITTER: Huizing M

PROVIDER: S-EPMC8175076 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Hermansky-Pudlak syndrome: Mutation update.

Huizing Marjan M Malicdan May C V MCV Wang Jennifer A JA Pri-Chen Hadass H Hess Richard A RA Fischer Roxanne R O'Brien Kevin J KJ Merideth Melissa A MA Gahl William A WA Gochuico Bernadette R BR

Human mutation 20200123 3

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 associ ...[more]

PMID: 31898847

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Project description:IntroductionHermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder characterized by defective biogenesis of lysosome-related organelles. The genetic types of HPS are associated with a spectrum of multisystemic clinical manifestations. Phenotypic features of HPS type 1 (HPS-1) or HPS-4, which are associated with defects in biogenesis of lysosome-related organelles complex-3 (BLOC-3), are generally more severe than those of HPS-3, HPS-5, or HPS-6, which are associated with defects in BLOC-2. A paucity of information is available about renal impairment in HPS. The objective of this study is to expand the understanding of kidney disease in HPS.MethodsMedical records and clinical data of patients with HPS evaluated at the National Institutes of Health Clinical Center from 1995 to 2020 were retrospectively reviewed. For patients with more than one visit, the most recent renal function and urinalysis tests were analyzed. Estimated glomerular filtration rate (eGFR) was calculated using standard equations (i.e., Chronic Kidney Disease Epidemiology Collaboration, Modification of Diet in Renal Disease). Kidney tissue sections from 5 patients with HPS-1 and 1 patient with HPS-6 were examined.ResultsRecords from 205 adults and 52 children with HPS were reviewed. Calculated eGFR of adult patients with different HPS types differed significantly, and calculated eGFR of pediatric and adult patients with BLOC-3 disorders was significantly lower than that of patients with BLOC-2 disorders. Linear regression analysis showed that renal function progressively decreases with age in patients with BLOC-3 or BLOC-2 disorders, but the rate of decline was more rapid in patients with BLOC-3 disorders compared to patients with BLOC-2 disorders. In adult patients with HPS-1, glucosuria was found in 4%, proteinuria in 12%, hematuria in 15%, high levels of urinary β2MG in 24%, and elevated urinary albumin to creatinine ratios in 9%. Histological examination of kidney tissue showed accumulation of intracellular deposits of ceroid lipofuscin in proximal renal tubular epithelial cells in patients with HPS-1. There was no evidence of fibrosis, and glomeruli, distal renal tubular epithelial cells, and interstitial regions appeared histologically normal.ConclusionMild impairment of renal function is a feature of HPS. Kidneys of patients with HPS-1 contain proximal renal tubular intracellular deposits and no histologic evidence of fibrosis. Consistent with other manifestations of HPS, the phenotype of renal impairment is relatively more pronounced in patients with BLOC-3 disorders than in patients with BLOC-2 disorders. Strategies to avoid nephrotoxicity or renal tubular injury and to protect renal function should be considered for patients with HPS irrespective of age.

Project description:RationaleIndividuals with Hermansky-Pudlak syndrome type 1 (HPS-1), an autosomal recessive disorder characterized by defective biogenesis of lysosome-related organelles, develop an accelerated form of progressive fibrotic lung disease. The etiology of pulmonary fibrosis associated with HPS-1 is unknown.ObjectivesTo investigate the potential pathogenesis of pulmonary fibrosis in HPS-1, lung cells and proteins from individuals with HPS-1 were studied.MethodsForty-one subjects with HPS-1 with and without pulmonary fibrosis were evaluated with pulmonary function tests, high-resolution computed tomography scan, and bronchoscopy. Bronchoalveolar lavage cells and analytes were analyzed.Measurements and main resultsConcentrations of total bronchoalveolar lavage cells and alveolar macrophages were significantly higher in epithelial lining fluid from subjects with HPS-1 with and without pulmonary fibrosis compared with healthy research volunteers. Concentrations of cytokines and chemokines (i.e., monocyte chemoattractant protein-1, macrophage inflammatory protein-1alpha, and granulocyte-macrophage colony-stimulating factor) in alveolar epithelial lining fluid were significantly higher in subjects with HPS-1 with and without pulmonary fibrosis compared with healthy research volunteers (P < 0.001). In vitro, HPS-1 pulmonary fibrosis alveolar macrophages, which did not express HPS1 mRNA, secreted significantly higher concentrations of monocyte chemoattractant protein-1, macrophage inflammatory protein-1alpha, and regulated upon activation, normal T cell expressed and secreted (RANTES) protein compared with normal cells (P = 0.001, P = 0.014, and P = 0.011, respectively). Pirfenidone suppressed HPS-1 alveolar macrophage cytokine and chemokine secretion in vitro in a dose-dependent manner.ConclusionsIn HPS-1, alveolar inflammation predominantly involves macrophages and is associated with high lung concentrations of cytokines and chemokines. HPS-1 alveolar macrophages provide a model system in which to study the pathogenesis and treatment of HPS pulmonary fibrosis.

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Hermansky-Pudlak syndrome: Mutation update.

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Hermansky-Pudlak syndrome: Mutation update.

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