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William A. Gahl - One of the best experts on this subject based on the ideXlab platform.

  • hermansky pudlak Syndrome and oculocutaneous albinism in chinese children with pigmentation defects and easy bruising
    Orphanet Journal of Rare Diseases, 2019
    Co-Authors: Bradley Power, Marjan Huizing, William A. Gahl, Kevin J Obrien, Wadih M Zein, Wendy J Introne, Carlos R Ferreira, Dong Chen, Joshi Stephen, May Christine V Malicdan
    Abstract:

    Determining the etiology of oculocutaneous albinism is important for proper clinical management and to determine prognosis. The purpose of this study was to genotype and phenotype eight adopted Chinese children who presented with oculocutaneous albinism and easy bruisability. The patients were evaluated at a single center; their ages ranged from 3 to 8 years. Whole exome or direct sequencing showed that two of the children had Hermansky-Pudlak Syndrome (HPS) type-1 (HPS-1), one had HPS-3, one had HPS-4, and four had non-syndromic oculocutaneous albinism associated with TYR variants (OCA1). Two frameshift variants in HPS1 (c.9delC and c.1477delA), one nonsense in HPS4 (c.416G > A), and one missense variant in TYR (c.1235C > T) were unreported. The child with HPS-4 is the first case with this subtype reported in the Chinese population. Hypopigmentation in patients with HPS was mild compared to that in OCA1 cases, who had severe pigment defects. Bruises, which may be more visible in patients with hypopigmentation, were found in all cases with either HPS or OCA1. Whole mount transmission electron microscopy demonstrated absent platelet dense granules in the HPS cases; up to 1.9 mean dense granules per platelet were found in those with OCA1. Platelet aggregation studies in OCA1 cases were inconclusive. Clinical manifestations of oculocutaneous albinism and easy bruisability may be observed in children with HPS or OCA1. Establishing definitive diagnoses in children presenting with these phenotypic features is facilitated by genetic testing. Non-syndromic oculocutaneous albinism and various HPS subtypes, including HPS-4, are found in children of Chinese ancestry.

  • Hermansky-Pudlak Syndrome and oculocutaneous albinism in Chinese children with pigmentation defects and easy bruising
    BMC, 2019
    Co-Authors: Bradley Power, Marjan Huizing, William A. Gahl, Wadih M Zein, Wendy J Introne, Kevin J. O’brien, Carlos R Ferreira, Dong Chen, Joshi Stephen, May Christine V Malicdan
    Abstract:

    Abstract Background Determining the etiology of oculocutaneous albinism is important for proper clinical management and to determine prognosis. The purpose of this study was to genotype and phenotype eight adopted Chinese children who presented with oculocutaneous albinism and easy bruisability. Results The patients were evaluated at a single center; their ages ranged from 3 to 8 years. Whole exome or direct sequencing showed that two of the children had Hermansky-Pudlak Syndrome (HPS) type-1 (HPS-1), one had HPS-3, one had HPS-4, and four had non-syndromic oculocutaneous albinism associated with TYR variants (OCA1). Two frameshift variants in HPS1 (c.9delC and c.1477delA), one nonsense in HPS4 (c.416G > A), and one missense variant in TYR (c.1235C > T) were unreported. The child with HPS-4 is the first case with this subtype reported in the Chinese population. Hypopigmentation in patients with HPS was mild compared to that in OCA1 cases, who had severe pigment defects. Bruises, which may be more visible in patients with hypopigmentation, were found in all cases with either HPS or OCA1. Whole mount transmission electron microscopy demonstrated absent platelet dense granules in the HPS cases; up to 1.9 mean dense granules per platelet were found in those with OCA1. Platelet aggregation studies in OCA1 cases were inconclusive. Conclusions Clinical manifestations of oculocutaneous albinism and easy bruisability may be observed in children with HPS or OCA1. Establishing definitive diagnoses in children presenting with these phenotypic features is facilitated by genetic testing. Non-syndromic oculocutaneous albinism and various HPS subtypes, including HPS-4, are found in children of Chinese ancestry

  • prolonged treatment with open label pirfenidone in hermansky pudlak Syndrome pulmonary fibrosis
    Molecular Genetics and Metabolism, 2018
    Co-Authors: Kevin J Obrien, William A. Gahl, Wendy J Introne, Orhan Akal, Tulay Akal, Adrian Barbu, Melissa Mcgowan, Melissa A Merideth, Samuel L Seward, Bernadette R Gochuico
    Abstract:

    Abstract Purpose Limited information is available regarding chronic treatment with pirfenidone, an anti-fibrotic drug. Effects of long-term open-label pirfenidone were evaluated in a small cohort with Hermansky-Pudlak Syndrome (HPS), a rare autosomal recessive disorder with highly penetrant pulmonary fibrosis. Results Three patients with HPS pulmonary fibrosis treated with open-label pirfenidone and twenty-one historical controls randomized to placebo were studied at a single center. Mean duration of treatment with pirfenidone for 3 patients with HPS pulmonary fibrosis was 13.1 years. Annual changes in FVC and DLCO with pirfenidone treatment were 0.46 and − 0.93% predicted, respectively. In comparison, historical controls randomized to receive placebo experienced mean annual changes in FVC and DLCO of −4.4 and − 2.3% predicted, respectively. High-resolution computed tomography (HRCT) scans revealed improved ground glass opacities with development of minimal interstitial reticulations in 1 patient after 12.8 years of treatment with pirfenidone. Slowly progressive increase in bilateral interstitial fibrosis developed in a different patient, who received pirfenidone for 18.1 years and died at 73 years of age due to HPS pulmonary fibrosis. Another patient treated with pirfenidone for 8.4 years had attenuated ground glass opacification on HRCT scan and improved oxygenation; this patient died due to chronic complications from colitis, and not pulmonary fibrosis. Adverse effects were generally limited to mild gastrointestinal discomfort and transient elevations of alanine aminotransferase in one patient. Conclusions Chronic treatment with pirfenidone may provide clinical benefit with few adverse effects for some patients with HPS pulmonary fibrosis. These results suggest that compassionate use of pirfenidone could be considered on a case-by-case basis for patients with HPS pulmonary fibrosis.

  • hermansky pudlak Syndrome with a novel genetic variant in hps1 and subsequent accelerated pulmonary fibrosis significance for phenocopy diseases
    Thorax, 2018
    Co-Authors: Oliver J Mcelvaney, Marjan Huizing, William A. Gahl, Paul Odonovan, Deirdre Horan, Mark P Logan, Emer P Reeves, Noel G Mcelvaney
    Abstract:

    The Hermansky-Pudlak Syndrome (HPS) is a collection of autosomal-recessive disorders characterised by tyrosinase-positive oculocutaneous albinism (OCA), bleeding diatheses and, in selected individuals, early-onset accelerated pulmonary fibrosis, neutropaenia and granulomatous colitis. We describe a young man who presented following a self-directed literature review prompted by severe bleeding complications following minor surgical and dental procedures in the context of OCA. HPS was clinically suspected, with subsequent genetic testing confirming biallelic mutations in the HPS1 gene. Of interest, this is the only described HPS type 1 patient with two different (compound heterozygote) splice site variants in HPS1 In addition to detailing a novel genetic result and outlining the progressive clinical course of disease in this case, we discuss the management of HPS, the prognostic value of subtype analysis and the technical difficulties relating to transplantation in the case of HPS-associated advanced pulmonary fibrosis. This case also illustrates the concept of lung phenocopy relationships and the potential for elucidating the pathogenesis of more common pulmonary disorders by studying genetic diseases that result in similar phenotypes. Furthermore, it re-emphasises the importance of the patient voice, particularly with regard to complex diagnoses and rare diseases.

  • galectin 3 interacts with the chi3l1 axis and contributes to hermansky pudlak Syndrome lung disease
    Journal of Immunology, 2018
    Co-Authors: Yang Zhou, William A. Gahl, Bernadette R Gochuico, Daniel S Yang, Tung Nguyen, Yueming Cao, Suchitra Kamle, Changmin Lee, Barry S Shea, Chun Geun Lee
    Abstract:

    Hermansky-Pudlak Syndrome (HPS) comprises a group of inherited disorders caused by mutations that alter the function of lysosome-related organelles. Pulmonary fibrosis is the major cause of morbidity and mortality in HPS-1 and HPS-4 patients. However, the mechanisms that underlie the exaggerated injury and fibroproliferative repair responses in HPS have not been adequately defined. In particular, although Galectin-3 (Gal-3) is dysregulated in HPS, its roles in the pathogenesis of HPS have not been adequately defined. In addition, although chitinase 3-like 1 (CHI3L1) and its receptors play major roles in the injury and repair responses in HPS, the ability of Gal-3 to interact with or alter the function of these moieties has not been evaluated. In this article, we demonstrate that Gal-3 accumulates in exaggerated quantities in bronchoalveolar lavage fluids, and traffics abnormally and accumulates intracellularly in lung fibroblasts and macrophages from bleomycin-treated pale ear, HPS-1-deficient mice. We also demonstrate that Gal-3 drives epithelial apoptosis when in the extracellular space, and stimulates cell proliferation and myofibroblast differentiation when accumulated in fibroblasts and M2-like differentiation when accumulated in macrophages. Biophysical and signaling evaluations also demonstrated that Gal-3 physically interacts with IL-13Rα2 and CHI3L1, and competes with TMEM219 for IL-13Rα2 binding. By doing so, Gal-3 diminishes the antiapoptotic effects of and the antiapoptotic signaling induced by CHI3L1 in epithelial cells while augmenting macrophage Wnt/β-catenin signaling. Thus, Gal-3 contributes to the exaggerated injury and fibroproliferative repair responses in HPS by altering the antiapoptotic and fibroproliferative effects of CHI3L1 and its receptor complex in a tissue compartment-specific manner.

Bernadette R Gochuico - One of the best experts on this subject based on the ideXlab platform.

  • prolonged treatment with open label pirfenidone in hermansky pudlak Syndrome pulmonary fibrosis
    Molecular Genetics and Metabolism, 2018
    Co-Authors: Kevin J Obrien, William A. Gahl, Wendy J Introne, Orhan Akal, Tulay Akal, Adrian Barbu, Melissa Mcgowan, Melissa A Merideth, Samuel L Seward, Bernadette R Gochuico
    Abstract:

    Abstract Purpose Limited information is available regarding chronic treatment with pirfenidone, an anti-fibrotic drug. Effects of long-term open-label pirfenidone were evaluated in a small cohort with Hermansky-Pudlak Syndrome (HPS), a rare autosomal recessive disorder with highly penetrant pulmonary fibrosis. Results Three patients with HPS pulmonary fibrosis treated with open-label pirfenidone and twenty-one historical controls randomized to placebo were studied at a single center. Mean duration of treatment with pirfenidone for 3 patients with HPS pulmonary fibrosis was 13.1 years. Annual changes in FVC and DLCO with pirfenidone treatment were 0.46 and − 0.93% predicted, respectively. In comparison, historical controls randomized to receive placebo experienced mean annual changes in FVC and DLCO of −4.4 and − 2.3% predicted, respectively. High-resolution computed tomography (HRCT) scans revealed improved ground glass opacities with development of minimal interstitial reticulations in 1 patient after 12.8 years of treatment with pirfenidone. Slowly progressive increase in bilateral interstitial fibrosis developed in a different patient, who received pirfenidone for 18.1 years and died at 73 years of age due to HPS pulmonary fibrosis. Another patient treated with pirfenidone for 8.4 years had attenuated ground glass opacification on HRCT scan and improved oxygenation; this patient died due to chronic complications from colitis, and not pulmonary fibrosis. Adverse effects were generally limited to mild gastrointestinal discomfort and transient elevations of alanine aminotransferase in one patient. Conclusions Chronic treatment with pirfenidone may provide clinical benefit with few adverse effects for some patients with HPS pulmonary fibrosis. These results suggest that compassionate use of pirfenidone could be considered on a case-by-case basis for patients with HPS pulmonary fibrosis.

  • galectin 3 interacts with the chi3l1 axis and contributes to hermansky pudlak Syndrome lung disease
    Journal of Immunology, 2018
    Co-Authors: Yang Zhou, William A. Gahl, Bernadette R Gochuico, Daniel S Yang, Tung Nguyen, Yueming Cao, Suchitra Kamle, Changmin Lee, Barry S Shea, Chun Geun Lee
    Abstract:

    Hermansky-Pudlak Syndrome (HPS) comprises a group of inherited disorders caused by mutations that alter the function of lysosome-related organelles. Pulmonary fibrosis is the major cause of morbidity and mortality in HPS-1 and HPS-4 patients. However, the mechanisms that underlie the exaggerated injury and fibroproliferative repair responses in HPS have not been adequately defined. In particular, although Galectin-3 (Gal-3) is dysregulated in HPS, its roles in the pathogenesis of HPS have not been adequately defined. In addition, although chitinase 3-like 1 (CHI3L1) and its receptors play major roles in the injury and repair responses in HPS, the ability of Gal-3 to interact with or alter the function of these moieties has not been evaluated. In this article, we demonstrate that Gal-3 accumulates in exaggerated quantities in bronchoalveolar lavage fluids, and traffics abnormally and accumulates intracellularly in lung fibroblasts and macrophages from bleomycin-treated pale ear, HPS-1-deficient mice. We also demonstrate that Gal-3 drives epithelial apoptosis when in the extracellular space, and stimulates cell proliferation and myofibroblast differentiation when accumulated in fibroblasts and M2-like differentiation when accumulated in macrophages. Biophysical and signaling evaluations also demonstrated that Gal-3 physically interacts with IL-13Rα2 and CHI3L1, and competes with TMEM219 for IL-13Rα2 binding. By doing so, Gal-3 diminishes the antiapoptotic effects of and the antiapoptotic signaling induced by CHI3L1 in epithelial cells while augmenting macrophage Wnt/β-catenin signaling. Thus, Gal-3 contributes to the exaggerated injury and fibroproliferative repair responses in HPS by altering the antiapoptotic and fibroproliferative effects of CHI3L1 and its receptor complex in a tissue compartment-specific manner.

  • Immunophenotypic and Ultrastructural Analysis of Mast Cells in Hermansky-Pudlak Syndrome Type-1: A Possible Connection to Pulmonary Fibrosis.
    PloS one, 2016
    Co-Authors: Arnold S. Kirshenbaum, Bernadette R Gochuico, Kevin J. O’brien, Glenn Cruse, Avanti Desai, Geethani Bandara, Maarten Leerkes, Chyi-chia Richard Lee, Elizabeth R. Fischer, Kelly D. Stone
    Abstract:

    Hermansky-Pudlak Syndrome type-1 (HPS-1) is an autosomal recessive disorder caused by mutations in HPS1 which result in reduced expression of the HPS-1 protein, defective lysosome-related organelle (LRO) transport and absence of platelet delta granules. Patients with HPS-1 exhibit oculocutaneous albinism, colitis, bleeding and pulmonary fibrosis postulated to result from a dysregulated immune response. The effect of the HPS1 mutation on human mast cells (HuMCs) is unknown. Since HuMC granules classify as LROs along with platelet granules and melanosomes, we set out to determine if HPS-1 cutaneous and CD34+ culture-derived HuMCs have distinct granular and cellular characteristics. Cutaneous and cultured CD34+-derived HuMCs from HPS-1 patients were compared with normal cutaneous and control HuMCs, respectively, for any morphological and functional differences. One cytokine-independent HPS-1 culture was expanded, cloned, designated the HP proMastocyte (HPM) cell line and characterized. HPS-1 and idiopathic pulmonary fibrosis (IPF) alveolar interstitium showed numerous HuMCs; HPS-1 dermal mast cells exhibited abnormal granules when compared to healthy controls. HPS-1 HuMCs showed increased CD63, CD203c and reduced mediator release following FcɛRI aggregation when compared with normal HuMCs. HPM cells also had the duplication defect, expressed FcɛRI and intracytoplasmic proteases and exhibited less mediator release following FcɛRI aggregation. HPM cells constitutively released IL-6, which was elevated in patients’ serum, in addition to IL-8, fibronectin-1 (FN-1) and galectin-3 (LGALS3). Transduction with HPS1 rescued the abnormal HPM morphology, cytokine and matrix secretion. Microarray analysis of HPS-1 HuMCs and non-transduced HPM cells confirmed upregulation of differentially expressed genes involved in fibrogenesis and degranulation. Cultured HPS-1 HuMCs appear activated as evidenced by surface activation marker expression, a decrease in mediator content and impaired releasibility. The near-normalization of constitutive cytokine and matrix release following rescue by HPS1 transduction of HPM cells suggests that HPS-1 HuMCs may contribute to pulmonary fibrosis and constitute a target for therapeutic intervention.

  • In vitro functional correction of Hermansky-Pudlak Syndrome type-1 by lentiviral-mediated gene transfer
    Molecular genetics and metabolism, 2014
    Co-Authors: Yasuhiro Ikawa, Marjan Huizing, William A. Gahl, Andrew R Cullinane, Bernadette R Gochuico, Richard A Hess, Heidi Dorward, Fabio Candotti
    Abstract:

    Abstract Hermansky–Pudlak Syndrome (HPS) is a genetic disorder characterized by oculocutaneous albinism, bleeding tendency and susceptibility to pulmonary fibrosis. No curative therapy is available. Genetic correction directed to the lungs, bone marrow and/or gastro-intestinal tract might provide alternative forms of treatment for the diseases multi-systemic complications. We demonstrate that lentiviral-mediated gene transfer corrects the expression and function of the HPS1 gene in patient dermal melanocytes, which opens the way to development of gene therapy for HPS.

  • Interstitial Lung Disease and Pulmonary Fibrosis in Hermansky-Pudlak Syndrome Type 2, an Adaptor Protein-3 Complex Disease
    2012
    Co-Authors: Bernadette R Gochuico, Marjan Huizing, Gretchen A Golas, Charles D Scher, Maria Tsokos, Stacey D Denver, Melissa J Frei-jones, William A. Gahl
    Abstract:

    Pulmonary fibrosis develops in Hermansky-Pudlak Syndrome (HPS) types 1 and 4. Limited information is available about lung disease in HPS type 2 (HPS-2), which is characterized by abnormal function of the adaptor protein-3 (AP-3) complex. To define lung disease in HPS-2, one child and two adults with HPS-2 were evaluated at the National Institutes of Health on at least two visits, and another child was evaluated at the University of Texas Health Science Center San Antonio. All four subjects with HPS-2 had findings of interstitial lung disease (ILD) on a high-resolution computed tomography scan of the chest. The predominant feature was ground glass opacification. Subject 1, a 14-year-old male, and subject 4, a 4-year-old male, had severe ILD, pulmonary fibrosis, secondary pulmonary hypertension and recurrent lung infections. Lung biopsy performed at 20 months of age in subject 1 revealed interstitial fibrosis and prominent type II pneumocyte hyperplasia without lamellar body enlargement. Subject 2, a 27-year-old male smoker, had mild ILD. Subject 3, a 22-year-old male nonsmoker and brother of subject 2, had minimal ILD. Severe impairment of gas exchange was found in subjects 1 and 4 and not in subjects 2 or 3. Plasma concentrations of transforming growth factorβ

Richard A. Spritz - One of the best experts on this subject based on the ideXlab platform.

  • hermansky pudlak Syndrome type 7 hps 7 results from mutant dysbindin a member of the biogenesis of lysosome related organelles complex 1 bloc 1
    Nature Genetics, 2003
    Co-Authors: Wei Li, Derek J Blake, Caroline L. Tinsley, Edward K. Novak, Naoki Oiso, Rashi Gautam, Richard A. Spritz, Qing Zhang, Edward P Obrien, Neal G Copeland
    Abstract:

    Hermansky-Pudlak Syndrome type 7 (HPS-7) results from mutant dysbindin, a member of the biogenesis of lysosome-related organelles complex 1 (BLOC-1)

  • hermansky pudlak Syndrome type 7 hps 7 results from mutant dysbindin a member of the biogenesis of lysosome related organelles complex 1 bloc 1
    Nature Genetics, 2003
    Co-Authors: Qing Zhang, Derek J Blake, Caroline L. Tinsley, Edward K. Novak, Naoki Oiso, Rashi Gautam, Richard A. Spritz, Edward P Obrien, Neal G Copeland, Nancy A Jenkins
    Abstract:

    Hermansky-Pudlak Syndrome (HPS; MIM 203300) is a genetically heterogeneous disorder characterized by oculocutaneous albinism, prolonged bleeding and pulmonary fibrosis due to abnormal vesicle trafficking to lysosomes and related organelles, such as melanosomes and platelet dense granules. In mice, at least 16 loci are associated with HPS, including sandy (sdy; ref. 7). Here we show that the sdy mutant mouse expresses no dysbindin protein owing to a deletion in the gene Dtnbp1 (encoding dysbindin) and that mutation of the human ortholog DTNBP1 causes a novel form of HPS called HPS-7. Dysbindin is a ubiquitously expressed protein that binds to alpha- and beta-dystrobrevins, components of the dystrophin-associated protein complex (DPC) in both muscle and nonmuscle cells. We also show that dysbindin is a component of the biogenesis of lysosome-related organelles complex 1 (BLOC-1; refs. 9-11), which regulates trafficking to lysosome-related organelles and includes the proteins pallidin, muted and cappuccino, which are associated with HPS in mice. These findings show that BLOC-1 is important in producing the HPS phenotype in humans, indicate that dysbindin has a role in the biogenesis of lysosome-related organelles and identify unexpected interactions between components of DPC and BLOC-1.

  • The Hermansky-Pudlak Syndrome 1 (HPS1) and HPS4 Proteins Are Components of Two Complexes, BLOC-3 and BLOC-4, Involved in the Biogenesis of Lysosome-related Organelles
    The Journal of biological chemistry, 2003
    Co-Authors: Pei Wen Chiang, Richard T. Swank, Naoki Oiso, Rashi Gautam, Richard A. Spritz
    Abstract:

    Abstract Hermansky-Pudlak Syndrome (HPS) is a genetic disease of lysosome, melanosome, and granule biogenesis. Mutations of six different loci have been associated with HPS in humans, the most frequent of which are mutations of the HPS1 and HPS4 genes. Here, we show that the HPS1 and HPS4 proteins are components of two novel protein complexes involved in biogenesis of melanosome and lysosome-related organelles: biogenesis of lysosome-related organelles complex-(BLOC) 3 and BLOC-4. The phenotypes of Hps1-mutant (pale-ear; ep) and Hps4-mutant (light-ear; le) mice and humans are very similar, and cells from ep and le mice exhibit similar abnormalities of melanosome morphology. HPS1 protein is absent from ep-mutant cells, and HPS4 from le-mutant cells, but le-mutant cells also lack HPS1 protein. HPS4 protein seems to be necessary for stabilization of HPS1, and the HPS1 and HPS4 proteins co-immunoprecipitate, indicating that they are in a complex. HPS1 and HPS4 do not interact directly in a yeast two-hybrid system, although HPS4 interacts with itself. In a partially purified vesicular/organellar fraction, HPS1 and HPS4 are both components of a complex with a molecular mass of ∼500 kDa, termed BLOC-3. Within BLOC-3, HPS1 and HPS4 are components of a discrete ∼200-kDa module termed BLOC-4. In the cytosol, HPS1 (but not HPS4) is part of yet another complex, termed BLOC-5. We propose that the BLOC-3 and BLOC-4 HPS1·HPS4 complexes play a central role in trafficking cargo proteins to newly formed cytoplasmic organelles.

  • positional cloning of a gene for hermansky pudlak Syndrome a disorder of cytoplasmic organelles
    Nature Genetics, 1996
    Co-Authors: Tu Bailin, Kazuyoshi Fukai, Guo Hong Feng, Jeni Mao, Edgar Frenk, Naoaki Tamura, Richard A. Spritz
    Abstract:

    Hermansky–Pudlak Syndrome (HPS) is an often–fatal autosomal recessive disease in which albinism, bleeding, and lysosomal storage result from defects of diverse cytoplasmic organelles: melanosomes, platelet dense bodies, and lysosomes. HPS is the most common single–gene disorder in Puerto Rico, with an incidence of 1 in 1,800. We have identified the HPS gene by positional cloning, and found homozygous frameshifts in this gene in Puerto Rican, Swiss, Irish and Japanese HPS patients. The HPS polypeptide is a novel transmembrane protein that is likely to be a component of multiple cytoplasmic organelles and that is apparently crucial for their normal development and function. The different clinical phenotypes associated with the different HPS frameshifts we observed suggests that differentially truncated HPS polypeptides may have somewhat different consequences for subcellular function.

Marjan Huizing - One of the best experts on this subject based on the ideXlab platform.

  • hermansky pudlak Syndrome and oculocutaneous albinism in chinese children with pigmentation defects and easy bruising
    Orphanet Journal of Rare Diseases, 2019
    Co-Authors: Bradley Power, Marjan Huizing, William A. Gahl, Kevin J Obrien, Wadih M Zein, Wendy J Introne, Carlos R Ferreira, Dong Chen, Joshi Stephen, May Christine V Malicdan
    Abstract:

    Determining the etiology of oculocutaneous albinism is important for proper clinical management and to determine prognosis. The purpose of this study was to genotype and phenotype eight adopted Chinese children who presented with oculocutaneous albinism and easy bruisability. The patients were evaluated at a single center; their ages ranged from 3 to 8 years. Whole exome or direct sequencing showed that two of the children had Hermansky-Pudlak Syndrome (HPS) type-1 (HPS-1), one had HPS-3, one had HPS-4, and four had non-syndromic oculocutaneous albinism associated with TYR variants (OCA1). Two frameshift variants in HPS1 (c.9delC and c.1477delA), one nonsense in HPS4 (c.416G > A), and one missense variant in TYR (c.1235C > T) were unreported. The child with HPS-4 is the first case with this subtype reported in the Chinese population. Hypopigmentation in patients with HPS was mild compared to that in OCA1 cases, who had severe pigment defects. Bruises, which may be more visible in patients with hypopigmentation, were found in all cases with either HPS or OCA1. Whole mount transmission electron microscopy demonstrated absent platelet dense granules in the HPS cases; up to 1.9 mean dense granules per platelet were found in those with OCA1. Platelet aggregation studies in OCA1 cases were inconclusive. Clinical manifestations of oculocutaneous albinism and easy bruisability may be observed in children with HPS or OCA1. Establishing definitive diagnoses in children presenting with these phenotypic features is facilitated by genetic testing. Non-syndromic oculocutaneous albinism and various HPS subtypes, including HPS-4, are found in children of Chinese ancestry.

  • Hermansky-Pudlak Syndrome and oculocutaneous albinism in Chinese children with pigmentation defects and easy bruising
    BMC, 2019
    Co-Authors: Bradley Power, Marjan Huizing, William A. Gahl, Wadih M Zein, Wendy J Introne, Kevin J. O’brien, Carlos R Ferreira, Dong Chen, Joshi Stephen, May Christine V Malicdan
    Abstract:

    Abstract Background Determining the etiology of oculocutaneous albinism is important for proper clinical management and to determine prognosis. The purpose of this study was to genotype and phenotype eight adopted Chinese children who presented with oculocutaneous albinism and easy bruisability. Results The patients were evaluated at a single center; their ages ranged from 3 to 8 years. Whole exome or direct sequencing showed that two of the children had Hermansky-Pudlak Syndrome (HPS) type-1 (HPS-1), one had HPS-3, one had HPS-4, and four had non-syndromic oculocutaneous albinism associated with TYR variants (OCA1). Two frameshift variants in HPS1 (c.9delC and c.1477delA), one nonsense in HPS4 (c.416G > A), and one missense variant in TYR (c.1235C > T) were unreported. The child with HPS-4 is the first case with this subtype reported in the Chinese population. Hypopigmentation in patients with HPS was mild compared to that in OCA1 cases, who had severe pigment defects. Bruises, which may be more visible in patients with hypopigmentation, were found in all cases with either HPS or OCA1. Whole mount transmission electron microscopy demonstrated absent platelet dense granules in the HPS cases; up to 1.9 mean dense granules per platelet were found in those with OCA1. Platelet aggregation studies in OCA1 cases were inconclusive. Conclusions Clinical manifestations of oculocutaneous albinism and easy bruisability may be observed in children with HPS or OCA1. Establishing definitive diagnoses in children presenting with these phenotypic features is facilitated by genetic testing. Non-syndromic oculocutaneous albinism and various HPS subtypes, including HPS-4, are found in children of Chinese ancestry

  • hermansky pudlak Syndrome with a novel genetic variant in hps1 and subsequent accelerated pulmonary fibrosis significance for phenocopy diseases
    Thorax, 2018
    Co-Authors: Oliver J Mcelvaney, Marjan Huizing, William A. Gahl, Paul Odonovan, Deirdre Horan, Mark P Logan, Emer P Reeves, Noel G Mcelvaney
    Abstract:

    The Hermansky-Pudlak Syndrome (HPS) is a collection of autosomal-recessive disorders characterised by tyrosinase-positive oculocutaneous albinism (OCA), bleeding diatheses and, in selected individuals, early-onset accelerated pulmonary fibrosis, neutropaenia and granulomatous colitis. We describe a young man who presented following a self-directed literature review prompted by severe bleeding complications following minor surgical and dental procedures in the context of OCA. HPS was clinically suspected, with subsequent genetic testing confirming biallelic mutations in the HPS1 gene. Of interest, this is the only described HPS type 1 patient with two different (compound heterozygote) splice site variants in HPS1 In addition to detailing a novel genetic result and outlining the progressive clinical course of disease in this case, we discuss the management of HPS, the prognostic value of subtype analysis and the technical difficulties relating to transplantation in the case of HPS-associated advanced pulmonary fibrosis. This case also illustrates the concept of lung phenocopy relationships and the potential for elucidating the pathogenesis of more common pulmonary disorders by studying genetic diseases that result in similar phenotypes. Furthermore, it re-emphasises the importance of the patient voice, particularly with regard to complex diagnoses and rare diseases.

  • In vitro functional correction of Hermansky-Pudlak Syndrome type-1 by lentiviral-mediated gene transfer
    Molecular genetics and metabolism, 2014
    Co-Authors: Yasuhiro Ikawa, Marjan Huizing, William A. Gahl, Andrew R Cullinane, Bernadette R Gochuico, Richard A Hess, Heidi Dorward, Fabio Candotti
    Abstract:

    Abstract Hermansky–Pudlak Syndrome (HPS) is a genetic disorder characterized by oculocutaneous albinism, bleeding tendency and susceptibility to pulmonary fibrosis. No curative therapy is available. Genetic correction directed to the lungs, bone marrow and/or gastro-intestinal tract might provide alternative forms of treatment for the diseases multi-systemic complications. We demonstrate that lentiviral-mediated gene transfer corrects the expression and function of the HPS1 gene in patient dermal melanocytes, which opens the way to development of gene therapy for HPS.

  • Interstitial Lung Disease and Pulmonary Fibrosis in Hermansky-Pudlak Syndrome Type 2, an Adaptor Protein-3 Complex Disease
    2012
    Co-Authors: Bernadette R Gochuico, Marjan Huizing, Gretchen A Golas, Charles D Scher, Maria Tsokos, Stacey D Denver, Melissa J Frei-jones, William A. Gahl
    Abstract:

    Pulmonary fibrosis develops in Hermansky-Pudlak Syndrome (HPS) types 1 and 4. Limited information is available about lung disease in HPS type 2 (HPS-2), which is characterized by abnormal function of the adaptor protein-3 (AP-3) complex. To define lung disease in HPS-2, one child and two adults with HPS-2 were evaluated at the National Institutes of Health on at least two visits, and another child was evaluated at the University of Texas Health Science Center San Antonio. All four subjects with HPS-2 had findings of interstitial lung disease (ILD) on a high-resolution computed tomography scan of the chest. The predominant feature was ground glass opacification. Subject 1, a 14-year-old male, and subject 4, a 4-year-old male, had severe ILD, pulmonary fibrosis, secondary pulmonary hypertension and recurrent lung infections. Lung biopsy performed at 20 months of age in subject 1 revealed interstitial fibrosis and prominent type II pneumocyte hyperplasia without lamellar body enlargement. Subject 2, a 27-year-old male smoker, had mild ILD. Subject 3, a 22-year-old male nonsmoker and brother of subject 2, had minimal ILD. Severe impairment of gas exchange was found in subjects 1 and 4 and not in subjects 2 or 3. Plasma concentrations of transforming growth factorβ

Edward K. Novak - One of the best experts on this subject based on the ideXlab platform.

  • aberrant lung structure composition and function in a murine model of hermansky pudlak Syndrome
    American Journal of Physiology-lung Cellular and Molecular Physiology, 2003
    Co-Authors: Timothy A Lyerla, Edward K. Novak, Michael E Rusiniak, Michael T Borchers, Gerald P Jahreis, Patricia J Ohtake, Richard T. Swank
    Abstract:

    Hermansky-Pudlak Syndrome (HPS) is a genetically heterogeneous inherited disease causing hypopigmentation and prolonged bleeding times. An additional serious clinical problem of HPS is the developm...

  • hermansky pudlak Syndrome type 7 hps 7 results from mutant dysbindin a member of the biogenesis of lysosome related organelles complex 1 bloc 1
    Nature Genetics, 2003
    Co-Authors: Qing Zhang, Derek J Blake, Caroline L. Tinsley, Edward K. Novak, Naoki Oiso, Rashi Gautam, Richard A. Spritz, Edward P Obrien, Neal G Copeland, Nancy A Jenkins
    Abstract:

    Hermansky-Pudlak Syndrome (HPS; MIM 203300) is a genetically heterogeneous disorder characterized by oculocutaneous albinism, prolonged bleeding and pulmonary fibrosis due to abnormal vesicle trafficking to lysosomes and related organelles, such as melanosomes and platelet dense granules. In mice, at least 16 loci are associated with HPS, including sandy (sdy; ref. 7). Here we show that the sdy mutant mouse expresses no dysbindin protein owing to a deletion in the gene Dtnbp1 (encoding dysbindin) and that mutation of the human ortholog DTNBP1 causes a novel form of HPS called HPS-7. Dysbindin is a ubiquitously expressed protein that binds to alpha- and beta-dystrobrevins, components of the dystrophin-associated protein complex (DPC) in both muscle and nonmuscle cells. We also show that dysbindin is a component of the biogenesis of lysosome-related organelles complex 1 (BLOC-1; refs. 9-11), which regulates trafficking to lysosome-related organelles and includes the proteins pallidin, muted and cappuccino, which are associated with HPS in mice. These findings show that BLOC-1 is important in producing the HPS phenotype in humans, indicate that dysbindin has a role in the biogenesis of lysosome-related organelles and identify unexpected interactions between components of DPC and BLOC-1.

  • hermansky pudlak Syndrome type 7 hps 7 results from mutant dysbindin a member of the biogenesis of lysosome related organelles complex 1 bloc 1
    Nature Genetics, 2003
    Co-Authors: Wei Li, Derek J Blake, Caroline L. Tinsley, Edward K. Novak, Naoki Oiso, Rashi Gautam, Richard A. Spritz, Qing Zhang, Edward P Obrien, Neal G Copeland
    Abstract:

    Hermansky-Pudlak Syndrome type 7 (HPS-7) results from mutant dysbindin, a member of the biogenesis of lysosome-related organelles complex 1 (BLOC-1)

  • ru2 and ru encode mouse orthologs of the genes mutated in human hermansky pudlak Syndrome types 5 and 6
    Nature Genetics, 2003
    Co-Authors: Qing Zhang, Edward K. Novak, Michael E Rusiniak, Naoki Oiso, Rashi Gautam, Edward P Obrien, Wei Li, Baohui Zhao, Sreenivasulu Chintala, Yuke Zhang
    Abstract:

    Hermansky-Pudlak Syndrome (HPS) is a genetically heterogeneous disease involving abnormalities of melanosomes, platelet dense granules and lysosomes. Here we have used positional candidate and transgenic rescue approaches to identify the genes mutated in ruby-eye 2 and ruby-eye mice (ru2 and ru, respectively), two 'mimic' mouse models of HPS. We also show that these genes are orthologs of the genes mutated in individuals with HPS types 5 and 6, respectively, and that their protein products directly interact. Both genes are previously unknown and are found only in higher eukaryotes, and together represent a new class of genes that have evolved in higher organisms to govern the synthesis of highly specialized lysosome-related organelles.

  • The Hermansky-Pudlak Syndrome 1 (HPS1) and HPS2 genes independently contribute to the production and function of platelet dense granules, melanosomes, and lysosomes.
    Blood, 2002
    Co-Authors: Lijun Feng, Edward K. Novak, Juan S. Bonifacino, Lisa M. Hartnell, Lucy M. Collinson, Richard T. Swank
    Abstract:

    Hermansky-Pudlak Syndrome (HPS) is an inherited hemorrhagic disease affecting the related subcellular organelles platelet dense granules, lysosomes, and melanosomes. The mouse genes for HPS, pale ear and pearl, orthologous to the human HPS1 and HPS2 (ADTB3A) genes, encode a novel protein of unknown function and the b3A subunit of the AP-3 adaptor complex, respectively. To test for in vivo interactions between these genes in the production and function of intracellular organelles, mice doubly homozygous for the 2 mutant genes were produced by appropriate breeding. Cooperation between the 2 genes in melanosome production was evident in increased hypopigmentation of the coat together with dramatic quantitative and qualitative alterations of melanosomes of the retinal pigment epithelium and choroid of double mutant mice. Lysosomal and platelet dense granule abnormalities, including hyposecretion of lysosomal enzymes from kidneys and depression of serotonin concentrations of platelet dense granules were likewise more severe in double than single mutants. Also, lysosomal enzyme concentrations were significantly increased in lungs of double mutant mice. Interaction between the 2 genes was specific in that effects on organelles were confined to melanosomes, lysosomes, and platelet dense granules. Together, the evidence indicates these 2 HPS genes function largely independently at the whole organism level to affect the production and function of all 3 organelles. Further, the increased lysosomal enzyme levels in lung of double mutant mice suggest a cause of a major clinical problem of HPS, lung fibrosis. Finally, doubly mutant HPS mice are a useful laboratory model for analysis of severe HPS phenotypes. (Blood. 2002;99:1651-1658)