Hermansky-Pudlak Syndrome and Chediak-Higashi Syndrome: Disorders of Vesicle Formation and Trafficking

2001 ◽  
Vol 86 (07) ◽  
pp. 233-245 ◽  
Author(s):  
Marjan Huizing ◽  
Yair Anikster ◽  
William Gahl
Keyword(s):  
Autosomal Recessive ◽  
Dense Body ◽  
Oculocutaneous Albinism ◽  
Clinical Findings ◽  
Vesicle Formation ◽  
Platelet Storage ◽  
A Subunit ◽  
Hermansky Pudlak Syndrome ◽  
Chediak Higashi Syndrome ◽  
Golgi Network

SummaryThe rare autosomal recessive metabolic disorders Hermanky-Pudlak syndrome (HPS) and Chediak-Higashi syndrome (CHS) share the clinical findings of oculocutaneous albinism and a platelet storage pool deficiency. In addition, HPS exhibits ceroid lipofuscinosis and CHS is characterized by infections and an accelerated phase. The two disorders result from defects in vesicles of lysosomal lineage. Of the two known HPS-causing genes, HPS1 has no recognizable function, while ADTB3A codes for a subunit of an adaptor complex responsible for new vesicle formation from the trans-Golgi network. Other HPS-causing genes are likely to exist. The only known CHS-causing gene, LYST, codes for a large protein of unknown function. In general, HPS appears to be a disorder of vesicle formation and CHS a defect in vesicle trafficking. These diseases and their variants mirror a group of mouse hypopigmentation mutants. The gene products involved will reveal how the melanosome, platelet dense body, and lysosome are formed and trafficked within cells.

scholarly journals Prospective Study of the Phenotypic and Mutational Spectrum of Ocular Albinism and Oculocutaneous Albinism

Genes ◽  
2021 ◽  
Vol 12 (4) ◽  
pp. 508
Author(s):  
Hwei Wuen Chan ◽  
Elena R. Schiff ◽  
Vijay K. Tailor ◽  
Samantha Malka ◽  
Magella M. Neveu ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Autosomal Recessive ◽  
Oculocutaneous Albinism ◽  
Whole Genome ◽  
Ocular Albinism ◽  
Panel Testing ◽  
Hereditary Disorders ◽  
Foveal Hypoplasia ◽  
Hermansky Pudlak Syndrome ◽  
Chediak Higashi Syndrome

Albinism encompasses a group of hereditary disorders characterized by reduced or absent ocular pigment and variable skin and/or hair involvement, with syndromic forms such as Hermansky–Pudlak syndrome and Chédiak–Higashi syndrome. Autosomal recessive oculocutaneous albinism (OCA) is phenotypically and genetically heterogenous (associated with seven genes). X-linked ocular albinism (OA) is associated with only one gene, GPR143. We report the clinical and genetic outcomes of 44 patients, from 40 unrelated families of diverse ethnicities, with query albinism presenting to the ocular genetics service at Moorfields Eye Hospital NHS Foundation Trust between November 2017 and October 2019. Thirty-six were children (≤ 16 years) with a median age of 31 months (range 2–186), and eight adults with a median age of 33 years (range 17–39); 52.3% (n = 23) were male. Genetic testing using whole genome sequencing (WGS, n = 9) or a targeted gene panel (n = 31) gave an overall diagnostic rate of 42.5% (44.4% (4/9) with WGS and 41.9% (13/31) with panel testing). Seventeen families had confirmed mutations in TYR (n = 9), OCA2, (n = 4), HPS1 (n = 1), HPS3 (n = 1), HPS6 (n = 1), and GPR143 (n = 1). Molecular diagnosis of albinism remains challenging due to factors such as missing heritability. Differential diagnoses must include SLC38A8-associated foveal hypoplasia and syndromic forms of albinism.

scholarly journals Correction of symptoms of platelet storage pool deficiency in animal models for Chediak-Higashi syndrome and Hermansky-Pudlak syndrome

Blood ◽  
1985 ◽  
Vol 66 (5) ◽  
pp. 1196-1201
Author(s):  
EK Novak ◽  
MP McGarry ◽  
RT Swank
Keyword(s):  
Bone Marrow ◽  
Animal Models ◽  
Dense Granule ◽  
Whole Body ◽  
Inherited Disorders ◽  
Humoral Factors ◽  
Storage Pool ◽  
Platelet Storage ◽  
Hermansky Pudlak Syndrome ◽  
Chediak Higashi Syndrome

Two human diseases of platelet storage pool deficiency (SPD), Hermansky- Pudlak syndrome and Chediak-Higashi syndrome, are recessively inherited disorders characterized by hypopigmentation, prolonged bleeding, and normal platelet counts accompanied by a reduction in dense granule number. We have recently described seven independent recessive mutations in the mouse regulated by separate genes which are likely animal models for human SPD. Reciprocal bone marrow transplants were carried out between normal C57BL/6J mice and two of these mutants, beige and pallid, in order to test whether the platelet defects are due to a defect in platelet progenitor cells or to humoral factors. Normal and congenic mutant mice were transplanted with marrow after 950 rad whole body radiation. The long bleeding times and low serotonin concentrations of the two mutants were converted to normal values after transplantation with normal marrow. Likewise, normal mice displayed symptoms of SPD when transplanted with mutant marrow. These studies demonstrate that with each of the two mutations, platelet SPD results from a defect in bone marrow precursor cells. Also, the studies suggest that in severe cases, platelet SPD may be successfully treated by bone marrow transplantation.

scholarly journals Chediak-Higashi Syndrome in Accelerated Phase, a Case Report

2021 ◽  
Vol 1 (1) ◽  
Author(s):  
Artriz R
Keyword(s):  
Hemophagocytic Syndrome ◽  
Respiratory Infections ◽  
Autosomal Recessive Inheritance ◽  
Oculocutaneous Albinism ◽  
Clinical Findings ◽  
Genetic Abnormalities ◽  
History Of ◽  
Chediak Higashi Syndrome ◽  
Lysosomal Transport ◽  
Pro Inflammatory Cytokines

Chediak-Higashi syndrome corresponds to a series of genetic abnormalities in lysosomal transport, of autosomal recessive inheritance, characterized by partial oculocutaneous albinism and recurrent infections,1 usually between 7 and 10 years of age the accelerated phase of the disease, where developing hemophagocytic syndrome, given by a set of clinical findings, laboratory and histological studies where phagocytosis is prominent,2 with a failure in the regulation of the immune system due to an excessive production of pro-inflammatory cytokines that coexists with a dysfunction of natural killer cells and T lymphocytes, which leads to lethal development. We present a case of a 13-month-old patient, natural and from Pregonero, with a family history of consanguinity, recurrent respiratory infections, and a characteristic phenotype of Chediak-Higashi syndrome, without prior diagnosis or controls for this pathology, who presents with hemophagocytic syndrome leading to its death in 20 days.

scholarly journals Novel HeterogenousCHS1Mutations Identified in Five Japanese Patients with Chediak-Higashi Syndrome

2010 ◽  
Vol 2010 ◽  
pp. 1-5 ◽  
Author(s):  
Fuminori Tanabe ◽  
Hirotake Kasai ◽  
Michiko Morimoto ◽  
Shigeharu Oh ◽  
Hidetoshi Takada ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Autosomal Recessive ◽  
Autosomal Recessive Disorder ◽  
Japanese Patients ◽  
Visual Disturbance ◽  
Oculocutaneous Albinism ◽  
Neurological Dysfunction ◽  
Nonsense Mutations ◽  
Chediak Higashi Syndrome ◽  
Exon 10

Chediak-Higashi syndrome (CHS) is a rare, autosomal recessive disorder characterized by oculocutaneous albinism, recurrent bacterial infections and progressive neurological dysfunction. We demonstrate novel heterogenous mutations ofCHS1, the responsive gene of CHS, identified in five Japanese patients with CHS. Patients 1, 2, and 3 were siblings, and they had albinism of the skin and hair. They all had a heterogenous two-base deletion (c.5541-5542 del AA, p.Q1847fsX1850) in exon 18. Patient 4 had a heterogenous single-base insertion (c.3944-3945 ins C, p.T1315fsX1331) in exon 10. The patient exhibited severe early-onset phenotype and suffered from hemophagocytic lymphohistiocytosis. Patient 5 had two heterogenous nonsense mutations; c.7982C>G, p.S2661X in exon 30 and c.8281A>T, p.R2761X in exon 31. The patient suffered from infections in childhood and had visual disturbance and albinism of the skin and hair. TheCHS1mutations described here have not been reported previously.

Defects in the cappuccino (cno) gene on mouse chromosome 5 and human 4p cause Hermansky-Pudlak syndrome by an AP-3–independent mechanism

Blood ◽  
2000 ◽  
Vol 96 (13) ◽  
pp. 4227-4235 ◽  
Author(s):  
Babette Gwynn ◽  
Steven L. Ciciotte ◽  
Susan J. Hunter ◽  
Linda L. Washburn ◽  
Richard S. Smith ◽  
...  
Keyword(s):  
Mouse Chromosome ◽  
Protein Trafficking ◽  
Dense Body ◽  
Spontaneous Mutation ◽  
Oculocutaneous Albinism ◽  
Chromosome 5 ◽  
Prolonged Bleeding ◽  
Independent Mechanism ◽  
Hermansky Pudlak Syndrome ◽  
Lysosome Related Organelles

Defects in a triad of organelles (melanosomes, platelet granules, and lysosomes) result in albinism, prolonged bleeding, and lysosome abnormalities in Hermansky-Pudlak syndrome (HPS). Defects in HPS1, a protein of unknown function, and in components of the AP-3 complex cause some, but not all, cases of HPS in humans. There have been 15 inherited models of HPS described in the mouse, underscoring its marked genetic heterogeneity. Here we characterize a new spontaneous mutation in the mouse, cappuccino (cno), that maps to mouse chromosome 5 in a region conserved with human 4p15-p16. Melanosomes ofcno/cno mice are immature and dramatically decreased in number in the eye and skin, resulting in severe oculocutaneous albinism. Platelet dense body contents (adenosine triphosphate, serotonin) are markedly deficient, leading to defective aggregation and prolonged bleeding. Lysosomal enzyme concentrations are significantly elevated in the kidney and liver. Genetic, immunofluorescence microscopy, and lysosomal protein trafficking studies indicate that the AP-3 complex is intact in cno/cno mice. It was concluded that the cappuccino gene encodes a product involved in an AP-3–independent mechanism critical to the biogenesis of lysosome-related organelles.

scholarly journals Chédiak-Higashi syndrome: presentation of seven cases

1998 ◽  
Vol 116 (6) ◽  
pp. 1873-1878 ◽  
Author(s):  
Eugénia Maria Grilo Carnide ◽  
Cristina Miuki Abe Jacob ◽  
Antonio Carlos Pastorino ◽  
Raquel Bellinati-Pires ◽  
Maria Beatriz Guimarães Costa ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Infectious Complications ◽  
Oculocutaneous Albinism ◽  
Recurrent Infections ◽  
Laboratory Findings ◽  
Public Care ◽  
Cytoplasmic Granules ◽  
Allergy And Immunology ◽  
Chediak Higashi Syndrome ◽  
Rare Autosomal Recessive Disease

CONTEXT: Chédiak-Higashi Syndrome (CHS) is a rare autosomal recessive disease characterized by recurrent infections, giant cytoplasmic granules, and oculocutaneous albinism. OBJECTIVE: To describe clinical and laboratory findings from CHS patients. DESIGN: Case report. SETTING: The patients were admitted into the Allergy and Immunology Unit of the Instituto da Criança, a tertiary public care institution. CASES REPORT: Seven patients had oculocutaneous albinism, recurrent infections and giant cytoplasmic granules in the leukocytes. One patient had low IgG levels and three showed impaired bactericidal activity of neutrophils. Six patients died of infectious complications during the accelerated phase. Therapy included ascorbic acid and antibiotics. Chemotherapy was used for the accelerated phase in two patients. Bone marrow transplantation (BMT) was proposed for one patient. DISCUSSION: The authors emphasize the need for early diagnosis and therapy of CHS. BMT should be indicated before the accelerated phase of the disease has developed.

Defects in the cappuccino (cno) gene on mouse chromosome 5 and human 4p cause Hermansky-Pudlak syndrome by an AP-3–independent mechanism

Blood ◽  
2000 ◽  
Vol 96 (13) ◽  
pp. 4227-4235 ◽  
Author(s):  
Babette Gwynn ◽  
Steven L. Ciciotte ◽  
Susan J. Hunter ◽  
Linda L. Washburn ◽  
Richard S. Smith ◽  
...  
Keyword(s):  
Mouse Chromosome ◽  
Protein Trafficking ◽  
Dense Body ◽  
Spontaneous Mutation ◽  
Oculocutaneous Albinism ◽  
Chromosome 5 ◽  
Prolonged Bleeding ◽  
Independent Mechanism ◽  
Hermansky Pudlak Syndrome ◽  
Lysosome Related Organelles

Abstract Defects in a triad of organelles (melanosomes, platelet granules, and lysosomes) result in albinism, prolonged bleeding, and lysosome abnormalities in Hermansky-Pudlak syndrome (HPS). Defects in HPS1, a protein of unknown function, and in components of the AP-3 complex cause some, but not all, cases of HPS in humans. There have been 15 inherited models of HPS described in the mouse, underscoring its marked genetic heterogeneity. Here we characterize a new spontaneous mutation in the mouse, cappuccino (cno), that maps to mouse chromosome 5 in a region conserved with human 4p15-p16. Melanosomes ofcno/cno mice are immature and dramatically decreased in number in the eye and skin, resulting in severe oculocutaneous albinism. Platelet dense body contents (adenosine triphosphate, serotonin) are markedly deficient, leading to defective aggregation and prolonged bleeding. Lysosomal enzyme concentrations are significantly elevated in the kidney and liver. Genetic, immunofluorescence microscopy, and lysosomal protein trafficking studies indicate that the AP-3 complex is intact in cno/cno mice. It was concluded that the cappuccino gene encodes a product involved in an AP-3–independent mechanism critical to the biogenesis of lysosome-related organelles.

scholarly journals Correction of symptoms of platelet storage pool deficiency in animal models for Chediak-Higashi syndrome and Hermansky-Pudlak syndrome

Blood ◽  
1985 ◽  
Vol 66 (5) ◽  
pp. 1196-1201 ◽  
Author(s):  
EK Novak ◽  
MP McGarry ◽  
RT Swank
Keyword(s):  
Bone Marrow ◽  
Animal Models ◽  
Dense Granule ◽  
Whole Body ◽  
Inherited Disorders ◽  
Humoral Factors ◽  
Storage Pool ◽  
Platelet Storage ◽  
Hermansky Pudlak Syndrome ◽  
Chediak Higashi Syndrome

Abstract Two human diseases of platelet storage pool deficiency (SPD), Hermansky- Pudlak syndrome and Chediak-Higashi syndrome, are recessively inherited disorders characterized by hypopigmentation, prolonged bleeding, and normal platelet counts accompanied by a reduction in dense granule number. We have recently described seven independent recessive mutations in the mouse regulated by separate genes which are likely animal models for human SPD. Reciprocal bone marrow transplants were carried out between normal C57BL/6J mice and two of these mutants, beige and pallid, in order to test whether the platelet defects are due to a defect in platelet progenitor cells or to humoral factors. Normal and congenic mutant mice were transplanted with marrow after 950 rad whole body radiation. The long bleeding times and low serotonin concentrations of the two mutants were converted to normal values after transplantation with normal marrow. Likewise, normal mice displayed symptoms of SPD when transplanted with mutant marrow. These studies demonstrate that with each of the two mutations, platelet SPD results from a defect in bone marrow precursor cells. Also, the studies suggest that in severe cases, platelet SPD may be successfully treated by bone marrow transplantation.

Chediak-Higashi syndrome is not due to a defect in microtubule-based lysosomal mobility

1993 ◽  
Vol 106 (1) ◽  
pp. 99-107 ◽  
Author(s):  
C.M. Perou ◽  
J. Kaplan
Keyword(s):  
Motor System ◽  
Autosomal Recessive ◽  
Phorbol Esters ◽  
Autosomal Recessive Disorder ◽  
Diagnostic Feature ◽  
Vesicle Formation ◽  
Cytoplasmic Ph ◽  
Intracellular Vesicle ◽  
Murine Homolog ◽  
Chediak Higashi Syndrome

Chediak-Higashi Syndrome is an autosomal recessive disorder that affects intracellular vesicle formation. The diagnostic feature of Chediak-Higashi Syndrome is the presence of ‘giant’ lysosomes clustered near the nucleus. Lysosome morphology in macrophages is maintained by microtubules and microtubule-based motors, such as kinesin. Dramatic changes in lysosome morphology can be induced by lowering cytoplasmic pH or by adding phorbol esters. When macrophages from beige mice (a murine homolog of Chediak-Higashi Syndrome) were subjected to these protocols they were able to alter their lysosomal distribution and morphology to the same degree as macrophages from control mice. These results indicate that lysosomes in Chediak cells are capable of interacting with the microtubule-based motor system, suggesting that the defective gene product is not an altered microtubular element involved in lysosomal movement.

Therapy refractory menorrhagia as first manifestation of Hermansky-Pudlak syndrome

2011 ◽  
Vol 31 (S 01) ◽  
pp. S61-S63
Author(s):  
S. Gehrisch ◽  
J. T. Tauer ◽  
R. Knöfler ◽  
J. Lohse
Keyword(s):  
Body Weight ◽  
Case Report ◽  
Clinical Response ◽  
Autosomal Recessive ◽  
Recombinant Factor Viia ◽  
Factor Viia ◽  
Single Injection ◽  
Oculocutaneous Albinism ◽  
Function Defect ◽  
Hermansky Pudlak Syndrome

Summary Introduction Oculocutaneous albinism (OCA) in combination with a platelet function defect caused by a disturbed release reaction from platelet δ-granules (storage pool defect – SPD) is typical for the autosomal recessive inherited Hermansky-Pudlak syndrome (HPS). Case report A girl (age: 13 years) with OCA was hospitalized with transfusion-requiring menorrhagia. The suspicion of HPS was confirmed by results of lumi-aggregometry. Suspecting a disorder in primary haemostasis treatment with tranexamic acid (10 mg/kg body weight every 8 h i. v.), desmopressin (0.3 μg/kg body weight every 8 to 12 h) and hormonal therapy (norethisterone) was started but the menorrhagia persisted. Clinical response was finally achieved by a single injection of 100 μg/kg body weight recombinant factor VIIa (rFVIIa). Conclusion The diagnosis of HPS should be suspected in patients with OCA and bleeding symptoms and is confirmed by the proof of SPD. In case of absent clinical response to desmopressin the application of rFVIIa should be considered. Hormones and antifibrinolytics are useful options in the treatment of extensive menorrhagia.

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