Wednesday 29 October 2003
Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder in which oculocutaneous albinism, bleeding, and lysosomal ceroid storage result from defects of multiple cytoplasmic organelles: melanosomes, platelet-dense granules, and lysosomes.
This syndrome is characterized by oculocutaneous albinism, bleeding diathesis, and storage of abnormal ceroid-like material in cells of the reticuloendothelial system. Pulmonary fibrosis or granulomatous colitis develops in some patients, probably because of the accumulation of undegraded macromolecules in the lysosomes of reticuloendothelial cells.
Hermansky-Pudlak syndrome (HPS) is genetically heterogeneous, and mutations in seven genes have been reported to cause HPS.
interstitial pulmonary fibrosis (restrictive lung disease)
granulomatous colitis (inflammatory bowel disease)
- albinism (creamy white skin with tanning possible)
- freckles in sun-exposed areas
- pigmented nevi
- hair color white to brown
- hair bulb tyrosinase present
- lifelong reduced visual acuity, legal blindness to low vision
- iris transillumination (variable)
- macular translucency (variable)
- iris color blue to brown
- ocular albinism
- foveal hypoplasia
- reduced visual acuity
- optic pathway misrouting
- platelet dysfunction
- bleeding diathesis
- absent dense bodies in platelets
- easy bruisability
- normal platelet counts
- normal prothrombin and partial chromoplastin times
- prolonged bleeding time
- gingival bleeding
pigmented reticuloendothelial cells
incomplete oculocutaneous albinism
abnormal aggregates of melanosomes within basal epidermal keratinocytes
Hermansky-Pudlak syndrome is a disorder of abnormal biogenesis of lysosomes and related organelles. Six genes are now identified causing HPS in humans (HPS-1 to HPS-6). Some HPS-gene products are part of distinct protein complexes: the adaptor complex AP-3, and six different BLOCs (Biogenesis of Lysosome-related Organelles Complex).
HPS1 (MIM.604982) at 10q23.1
HPS2: AP3B1 (MIM.603401) at Chr.5
HPS3 (MIM.606118) at 3q24
HPS4 (MIM.606682) at Chr.22
HPS5 (MIM.607521) at 11p15-p13
HPS6 (MIM.607522) at 10q24.32
HPS7: DTNBP1 (MIM.607145) at 6p22.3
HPS8: homozygous germline mutation in BLOC1S3
- BLOC1S3 encodes a subunit of the biogenesis of lysosome-related organelles complex 1 (BLOC-1).
- Mutations in other BLOC-1 subunits have been associated with an HPS phenotype in humans and/or mouse.
HPS to extensively characterize each subtype. Clinically, all patients show oculocutaneous albinism and storage pool deficiency. HPS-1 and HPS-4 also exhibit occasional granulomatous colitis and fatal pulmonary fibrosis. HPS-2 patients show persistent neutropenia and childhood infections. HPS-3, and perhaps HPS-5 and HPS-6 patients have a milder form of the disease with occasional granulomatous colitis.
The Hermansky-Pudlak syndrome was the first inherited defect in the coat-protein complexes in the vesicle to be identified.
The common denominator is deficient genesis or abnormal function of lysosomes or related cellular organelles: a disturbance in the maturation of melanosomes results in hypopigmentation, whereas a deficiency of platelet dense granules causes a chronic bleeding problem owing to defective secretion of compounds essential for activation of platelets.
Fibroblasts from the patients displayed drastically reduced concentrations of AP-3 and, as a consequence, increased surface expression of several lysosomal-membrane proteins. These findings provide insight into the function of the AP-3 complex and are evidence that AP-3 has a role in the transport of transmembrane proteins destined for the lysosomes.
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