Hermansky-Pudlak Syndrome Subtypes Research Articles

HERMANSKY-PUDLAK SYNDROME TYPE 6 (HPS6) AND RENAL FAILURE: A RARE GENETIC DISEASE

Hermansky-Pudlak syndrome (HPS) is a group of 10 autosomal recessive inherited diseases. Most patients exhibit albinism with nystagmus, visual acuity loss, and a platelet storage pool deciency with bleeding diathesis. The severity and variety of other clinical features depend on the HPS subtype. We report a 24-year-old male with end-stage renal disease of unknown etiology and history of oculocutaneous albinism and bleeding diathesis. Two of his siblings also had oculocutaneous albinism. The diagnostic workup for renal impairment was unremarkable. Further genetic testing revealed a homozygous novel nonsense mutation in the HPS6 gene. Additionally, a heterozygous variant of uncertain signicance was identied in the HPS5 gene. Renal failure is an uncommon clinical feature in HPS. To our knowledge, this is the rst case that describes the association of HPS types 5 and 6 and renal failure

New insights into the pathogenesis of Hermansky–Pudlak syndrome

Hermansky-Pudlak syndrome (HPS) is characterized by defects of multiple tissue-specific lysosome-related organelles (LROs), typically manifesting with oculocutaneous albinism or ocular albinism, bleeding tendency, and in some cases with pulmonary fibrosis, inflammatory bowel disease or immunodeficiency, neuropsychological disorders. Eleven HPS subtypes in humans and at least 15subtypes in mice have been molecularly identified. Current understanding of the underlying mechanisms of HPS is focusing on the defective biogenesis of LROs. Compelling evidences have shown that HPS protein-associated complexes (HPACs) function in cargo transport, cargo recycling, and cargo removal to maintain LRO homeostasis. Further investigation on the molecular and cellular mechanism of LRO biogenesis and secretion will be helpful for better understanding of its pathogenesis and for the precise intervention of HPS.

Hermansky-Pudlak syndrome subtype 5 (HPS-5): Safety of cardiac catheterization in patients with a bleeding diathesis

Hermansky-Pudlak syndrome subtype 5 (HPS-5): Safety of cardiac catheterization in patients with a bleeding diathesis

HPS1 Regulates the Maturation of Large Dense Core Vesicles and Lysozyme Secretion in Paneth Cells.

HPS1, a BLOC-3 subunit that acts as a guanine nucleotide exchange factor of Rab32/38, may play a role in the removal of VAMP7 during the maturation of large dense core vesicles of Paneth cells. Loss of HPS1 impairs lysozyme secretion and alters the composition of intestinal microbiota, which may explain the susceptibility of HPS-associated inflammatory bowel disease. Hermansky-Pudlak syndrome (HPS) is characterized by oculocutaneous albinism, bleeding tendency, and other chronic organ lesions due to defects in tissue-specific lysosome-related organelles (LROs). For some HPS subtypes, such as HPS-1, it is common to have symptoms of HPS-associated inflammatory bowel disease (IBD). However, its underlying mechanism is largely unknown. HPS1 is a subunit of the BLOC-3 complex which functions in the biogenesis of LROs. Large dense core vesicles (LDCVs) in Paneth cells of the intestine are a type of LROs. We here first report the abnormal LDCV morphology (increased number and enlarged size) in HPS1-deficient pale ear (ep) mice. Similar to its role in melanosome maturation, HPS1 plays an important function in the removal of VAMP7 from LDCVs to promote the maturation of LDCVs. The immature LDCVs in ep mice are defective in regulated secretion of lysozyme, a key anti-microbial peptide in the intestine. We observed changes in the composition of intestinal microbiota in both HPS-1 patients and ep mice. These findings provide insights into the underlying mechanism of HPS-associated IBD development, which may be implicated in possible therapeutic intervention of this devastating condition.

Partial albinism and immunodeficiency in patients with Hermansky‐Pudlak Type II: Introducing 2 novel mutations

Hermansky-Pudlak Syndrome (HPS) (OMIM: #608233) is a rare genetic disorder firstly described in 1959 by Frantisek Hermansky and Paulus Pudlak. HPS, which has been classified into ten different subtypes based on causative genes, clinically varies from mild to severe. The common clinical manifestations of all HPS subtypes are oculocutaneousalbinism, platelets dysfunction leads to bleeding tendency and/or the other appearances such as granulomatous, and pulmonary fibrosis.

Hermansky-Pudlak syndrome: Mutation update.

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.

A novel mutation causes Hermansky-Pudlak syndrome type 4 with pulmonary fibrosis in 2 siblings from China

Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive multisystem disorder characterized by oculocutaneous albinism (OCA) and bleeding diathesis, although it displays both genetic and phenotypic heterogeneity. Several genetic subtypes of HPS have been identified in human; however, the characterizations of HPS type 4 (HPS-4) genotype and phenotype remain unclear. This study was aimed to identify gene mutation responsible for HPS-4 with pulmonary fibrosis (PF).Two Chinese siblings in their 50 s afflicted with OCA and progressive dyspnea were recruited and underwent clinical and genetic examinations. In both patients, chest high-resolution computerized tomography showed severe interstitial PF in bilateral lung fields, and the pulmonary function test indicated restrictive lung disease. A novel homozygous frameshift mutation (NM_022081: c.630dupC; p.A211fs) in the HPS4 gene was identified by whole-exome sequencing analysis followed by Sanger DNA sequencing, and it segregated with the phenotypes. The c.630dupC mutation was not found in unaffected healthy controls. The patients were considered as HPS-4 with interstitial PF and eventually died of respiratory failure.This is the first report on the genotype and clinical phenotype of HPS-4 in China. Our results demonstrate the association between a novel frameshift mutation in HPS4 and severe PF with poor prognosis in HPS is presented.

Cellular and molecular defects in a patient with Hermansky-Pudlak syndrome type 5.

Hermansky-Pudlak syndrome (HPS) is a heterogeneous group of genetic disorders typically manifesting with tyrosinase-positive oculocutaneous albinism, bleeding diathesis, and pulmonary fibrosis, in some subtypes. Most HPS subtypes are associated with defects in Biogenesis of Lysosome-related Organelle Complexes (BLOCs), which are groups of proteins that function together in the formation and/or trafficking of lysosomal-related endosomal compartments. BLOC-2, for example, consists of the proteins HPS3, HPS5, and HPS6. Here we present an HPS patient with defective BLOC-2 due to a novel intronic mutation in HPS5 that activates a cryptic acceptor splice site. This mutation leads to the insertion of nine nucleotides in-frame and results in a reduced amount of HPS5 at the transcript and protein level. In studies using skin fibroblasts derived from the proband and two other individuals with HPS-5, we found a perinuclear distribution of acidified organelles in patient cells compared to controls. Our results suggest the role of HPS5 in the endo-lysosomal dynamics of skin fibroblasts.

Novel mutation in two brothers with Hermansky Pudlak syndrome type 3

Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder causing oculocutaneous albinism, bleeding disorder and ceroid lipofuscinosis. Platelets from HPS patients are characterized by impaired secretion of dense (δ)-bodies (CD63). Meanwhile, there are ten known human HPS genes, each leading to a particular clinical HPS subtype (HPS1-HPS10).We report on two Turkish brothers showing typical HPS phenotype comprising oculocutaneous albinism and bleeding symptoms. Pathological bleeding time as well as platelet aggregometry analyses revealed impaired platelet function. The brothers demonstrated absence of platelet δ-granule secretion as measured by flow cytometry. Using molecular genetic analyses, a novel homozygous 1bp-deletion in the HPS3 gene was identified in both brothers. In addition, the younger brother with HPS3 demonstrated psychomotoric retardation and cranial gliosis (magnetic resonance imaging, MRI). Array-CGH analysis revealed a de novo 0.482Mb deletion on chromosome 17 which is not present in his brother and parents.In this study, we identified a novel 1bp-deletion in the HPS3 gene causing HPS3 phenotype in two brothers. In patients with oculocutaneous albinism and increased bleeding symptoms platelet function should be analyzed. The identification of the molecular genetic defect allows the classification to a particular HPS subtype and is important for therapy and prognosis.

Natural killer cell activity and dysfunction in Hermansky‐Pudlak syndrome

Hermansky-Pudlak syndrome (HPS) encompasses disorders with abnormal function of lysosomes and lysosome-related organelles, and some patients who develop immunodeficiency. The basic mechanisms contributing to immune dysfunction in HPS are ill-defined. We analysed natural killer (NK) cells from patients diagnosed with HPS-1, HPS-2, HPS-4, and an unreported HPS subtype. NK cells from an HPS-2 and an unreported HPS subtype share a similar cellular phenotype with defective granule release and cytotoxicity, but differ in cytokine exocytosis. Defining NK cell activity in several types of HPS provides insights into cellular defects of the disorder and understanding of mechanisms contributing to HPS pathogenesis.

BLOC-2 targets recycling endosomal tubules to melanosomes for cargo delivery.

Hermansky-Pudlak syndrome (HPS) is a group of disorders characterized by the malformation of lysosome-related organelles, such as pigment cell melanosomes. Three of nine characterized HPS subtypes result from mutations in subunits of BLOC-2, a protein complex with no known molecular function. In this paper, we exploit melanocytes from mouse HPS models to place BLOC-2 within a cargo transport pathway from recycling endosomal domains to maturing melanosomes. In BLOC-2-deficient melanocytes, the melanosomal protein TYRP1 was largely depleted from pigment granules and underwent accelerated recycling from endosomes to the plasma membrane and to the Golgi. By live-cell imaging, recycling endosomal tubules of wild-type melanocytes made frequent and prolonged contacts with maturing melanosomes; in contrast, tubules from BLOC-2-deficient cells were shorter in length and made fewer, more transient contacts with melanosomes. These results support a model in which BLOC-2 functions to direct recycling endosomal tubular transport intermediates to maturing melanosomes and thereby promote cargo delivery and optimal pigmentation.

Dysregulation of Galectin-3. Implications for Hermansky-Pudlak Syndrome Pulmonary Fibrosis

The etiology of Hermansky-Pudlak syndrome (HPS) pulmonary fibrosis (HPSPF), a progressive interstitial lung disease with high mortality, is unknown. Galectin-3 is a β-galactoside-binding lectin with profibrotic effects. The objective of this study was to investigate the involvement of galectin-3 in HPSPF. Galectin-3 was measured by ELISA, immunohistochemistry, and immunoblotting in human specimens from subjects with HPS and control subjects. Mechanisms of galectin-3 accumulation were studied by quantitative RT-PCR, Northern blot analysis, membrane biotinylation assays, and rescue of HPS1-deficient cells by transfection. Bronchoalveolar lavage galectin-3 concentrations were significantly higher in HPSPF compared with idiopathic pulmonary fibrosis or that from normal volunteers, and correlated with disease severity. Galectin-3 immunostaining was increased in HPSPF compared with idiopathic pulmonary fibrosis or normal lung tissue. Fibroblasts from subjects with HPS subtypes associated with pulmonary fibrosis had increased galectin-3 protein expression compared with cells from nonfibrotic HPS subtypes. Galectin-3 protein accumulation was associated with reduced Galectin-3 mRNA, normal Mucin 1 levels, and up-regulated microRNA-322 in HPSPF cells. Membrane biotinylation assays showed reduced galectin-3 and normal Mucin 1 expression at the plasma membrane in HPSPF cells compared with control cells, which suggests that galectin-3 is mistrafficked in these cells. Reconstitution of HPS1 cDNA into HPS1-deficient cells normalized galectin-3 protein and mRNA levels, as well as corrected galectin-3 trafficking to the membrane. Intracellular galectin-3 levels are regulated by HPS1 protein. Abnormal accumulation of galectin-3 may contribute to the pathogenesis of HPSPF.

The Hermansky-Pudlak Syndrome: Clinical Features and Imperatives from an Ophthalmic Perspective

The Hermansky-Pudlak Syndrome (HPS) is a rare, autosomal recessive condition comprising nine genetically heterogeneous entities that feature oculocutaneous albinism (OCA) and bleeding tendency as their principal clinical manifestations. The pathogenesis of HPS involves disturbances in the biogenesis and trafficking of lysosome-related organelles. While the ophthalmologist is trained to address the ocular manifestations of OCA, it is critical for the provider to consider HPS when examining OCA patients as its systemic sequelae may be associated with morbidity and mortality. If there is suspicion of HPS in a patient with albinism, the ophthalmologist should enlist the aid of consultants to confirm the diagnosis and monitor for systemic features. As the nine HPS subtypes explored in this article vary widely in the character and severity of their associated systemic manifestations, some authors advocate determining the specific gene defect in each HPS patient in order to optimize care and provide anticipatory guidance.

Patients with Hermansky-Pudlak Syndrome Show Various Phenotypes Caused by Novel Mutations,

Abstract 3286▪▪This icon denotes a clinically relevant abstract Background:Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder causing oculocutaneous albinism, bleeding disorder and ceroid lipofuscinosis. Platelets from HPS patients are characterized by impaired secretion of dense (δ)-bodies (CD63). Neutropenia and susceptibility to recurrent infections were exclusively observed in HPS2 patients so far. There are eight known human HPS genes (HPS1-HPS8), each leading to a particular clinical HPS subtype (HPS1-HPS8). Patients/Results:The patients show a typical HPS phenotype concerning oculocutaneous albinism and bleeding symptoms. In vivo-, in vitro bleeding time and platelet aggregometry analyses revealed impaired platelet function. We identified HPS3 in two Turkish brothers and HPS2 in a girl from the United Emirates. Both brothers with HPS3 demonstrated absence of platelet δ-granule secretion measured by flow cytometry analysis. A novel 1 bp-deletion in the HPS3 gene was identified in both brothers. In addition, one brother with HPS3 demonstrated psychomotoric retardation. MRI scan revealed cranial gliosis. Interestingly, array-CGH analysis revealed a 0.7 Mb deletion on chromosome 17 which had not been identified in the other brother and which seems to have caused the cranial gliosis.The girl with HPS2 suffered from life-threatening bleeding after tonsillectomy leading to severe asphyxia, resuscitation and finally, to mental retardation. Flow cytometry analysis demonstrated impaired platelet δ-granule secretion with a typical pattern for HPS2. CD63 expression was already increased on resting platelets, but there was only little increase after thrombin stimulation. Interestingly, only a NK-CD107 partial degranulation defect was diagnosed. So far, clinical symptoms of immunodeficiency are not obvious. Molecular genetic analyses revealed a novel 2 bp-deletion in the last exon of HPS2 leading to a frameshift and a prolonged altered protein. The location of the deletion at the very C-terminal end may prevent a complete loss of the HPS2 protein leading to a less pronounced severity of immunodeficiency as in other HPS2 patients. Conclusion:Patients with oculocutaneous albinism should be investigated for increased clinical bleeding symptoms. In case of increased bleeding symptoms, analyses of primary hemostasis should be initiated to confirm HPS. Using flow cytometry analyses HPS2 can be distinguished from the other subtypes of HPS. Molecular genetic investigations should be performed to differentiate the various subtypes of HPS which is important for therapy and prognosis. The HPS3 patient`s mental retardation seemed to be caused by an additional deletion. The identification of the molecular genetic defect helps to understand the patients` various clinical phenotypes. Disclosures:Zieger:Novo Nordisk: Research Funding.

Novel mutations in the HPS1 gene among Puerto Rican patients

Hermansky-Pudlak syndrome (HPS) is a disorder of oculocutaneous albinism (OCA) and platelet storage pool deficiency. Eight different disease-causing genes have been identified, whose gene products are thought to be involved in the biogenesis of lysosome-related organelles. HPS type 1 (HPS-1) is the most common HPS subtype in Puerto Rico, with a frequency of 1:1800 in the northwest of the island due to a founder mutation, i.e. a 16-bp duplication in exon 15 of the HPS1 gene (c.1472_1487dup16; p.H497QfsX90). We identified three Puerto Rican HPS-1 patients who carried compound heterozygous HPS1 mutations. One patient was heterozygous for c.937G>A, causing a missense mutation (p.G313S) at the 3 splice junction of exon 10. This mutation resulted in activation of a cryptic intronic splice site causing an aberrantly spliced HPS1 mRNA that included 144-bp of intronic sequence, producing 11 novel amino acids followed by a stop codon. The other two patients were heterozygous for the previously reported c.972delC in HPS1, resulting in a frameshift and a premature stop codon (p.M325WfsX6). These findings indicate that, among Puerto Ricans, other HPS1 mutations apart from the 16-bp duplication should be considered in the analysis of this population.

Compound Heterozygous Mutations in 2 Siblings with Hermansky-Pudlak Syndrome Type 1 (HPS1)

Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder causing oculocutaneous albinism, bleeding disorder and ceroid lipofuscinosis. Platelets from HPS patients are characterized by the absence of dense (delta)-bodies. There are eight known human HPS GENES (HPS1-HPS8), each leading to a particular clinical HPS subtype. Restrictive lung disease, granulomatous colitis and cardiomyopathy have been described in HPS1 patients. We identified HPS1 in Russian and in German siblings. All four patients show a typical HPS phenotype. The two older Russian patients demonstrate excessive bleeding after tooth extractions, recurrent epistaxis and hematomas. The two younger German patients suffer only from hematomas, so far. Patients' platelets showed severe pathological agglutination/aggregation. Flow cytometry analysis demonstrated absence of platelet delta-granule secretion. Three different mutations in the HPS1 gene were found in the two families. Two mutations, p.H119delC and p.Q397delC identified in the Russian siblings had been previously described. The German siblings presented with a novel frameshift mutation (p.Q32_S33delCAGT) and the known p.Q397delC mutation. Patients with oculocutaneous albinism should be investigated for increased clinical bleeding symptoms. In case of increased bleeding symptoms, analyses of primary hemostasis should be initiated to confirm HPS. Molecular genetic investigations should be performed to distinguish the different subtypes of HPS which is important for therapy and prognosis.

Clinical and cellular characterisation of Hermansky–Pudlak syndrome type 6

Background:In the last decade, Hermansky–Pudlak syndrome (HPS) has arisen as an instructive disorder for cell biologists to study the biogenesis of lysosome related organelles (LROs). Of the eight human HPS...

Hermansky–Pudlak syndrome in two African‐American brothers

Hermansky-Pudlak syndrome (HPS) is an autosomal recessive disorder characterized by oculocutaneous albinism, a bleeding disorder, and, in some patients, granulomatous colitis and/or a fatal pulmonary fibrosis. There are eight different subtypes of HPS, each due to mutations in one of eight different genes, whose functions are thought to involve intracellular vesicle formation and trafficking. HPS has been identified in patients of nearly all ethnic groups, though it has primarily been associated with patients of Puerto Rican, Northern European, Japanese and Israeli descent. We report on the diagnosis of HPS type 1 in two African-American patients. Both brothers carried compound heterozygous mutations in HPS1: previously reported p.M325WfsX6 (c.972delC) and a novel silent mutation p.E169E (c.507G > A), which resulted in a splice defect. HPS may be under-diagnosed in African-American patients and other ethnic groups. A history of easy bruising or evidence of a bleeding disorder, combined with some degree of hypopigmentation, should prompt investigation into the diagnosis of HPS.

Platelet alpha granules in BLOC-2 and BLOC-3 subtypes of Hermansky-Pudlak syndrome

Hermansky-Pudlak syndrome (HPS) is a disorder of lysosome-related organelle biogenesis that displays genetic locus heterogeneity. The eight known HPS proteins combine in functional complexes, two of which are called BLOC-2 and BLOC-3; a BLOC is a Biogenesis of Lysosome-related Organelles Complex. Organelles affected in HPS include the melanosome, resulting in hypopigmentation, and the platelet delta (dense) granule, resulting in prolonged bleeding times. Whole mount electron microscopy (EM) detects the absence of platelet delta granules and confirms the diagnosis of HPS. To date, the status of other organelles and granules in HPS platelets has not been documented. We performed ultrastructural studies on platelets of patients with different genetic forms of HPS, specifically those comprising the BLOC-2 and BLOC-3 subtypes. No differences in distribution, size or quantity of other platelet organelles and membrane structures could be detected in our patients. Since alpha and delta granules are formed from multivesicular bodies in the megakaryocyte, and since only delta granules are defective in HPS, we conclude that HPS genes function within the portion of delta granule biogenesis that has diverged from that of alpha granules. Thus, it is unlikely that the generalized bleeding diathesis of HPS is attributed to a deficiency of alpha granules.

Ocular Pathologic Features of Hermansky-Pudlak Syndrome Type 1 in an Adult

Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disease, characterized by a triad of oculocutaneous albinism (OCA), bleeding diathesis due to deficiency of dense bodies in platelets, and lysosomal accumulation of ceroid lipofuscin.1 Seven genetic subtypes of HPS have been identified in humans2; HPS1 on chromosome 10q23 is the most common and represents a founder effect in northwest Puerto Rico.1 The clinical features of HPS and its ophthalmic involvement3,4 are well documented, but no ocular histopathology has been published (to our knowledge). Herein, we describe the ocular histopathology of an adult patient with HPS type 1 (HPS-1).