Hermansky-Pudlak Syndrome

El–Chemaly, Souheil; Young, Lisa R.

doi:10.1016/j.ccm.2016.04.012

Cited by 93 publications

(96 citation statements)

References 41 publications

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“…20,22,43 Up to now, 10 genes have been identified as causative for HPS in humans, whose mutation predicts the severity and diversity of symptoms. 8,16,44,45 Yet, there is still a number of patients presenting with HPS of unknown origin. The identification of most of the genes involved in human HPS have been greatly facilitated by the availability of HPS mouse disease models.…”

Section: Discussionmentioning

confidence: 99%

“…[5][6][7] In addition to the bleeding disorder, HPS is associated with oculocutaneous albinism and variable other serious complications such as immune deficiency or lung fibrosis depending whether the mutated gene also affects other organelles and cell types. 7,8 DGs belong to the family of lysosome related organelles (LRO), characterized by an acidic pH and the presence of lysosomalassociated membrane proteins (LAMPs), but their biogenesis differs from ubiquitous lysosomes. Because LROs also include, among others, the melanosomes in melanocytes, it has long been suggested that melanosomes and DGs share similar biogenesis routes.…”

Section: Introductionmentioning

confidence: 99%

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Combined deficiency of RAB32 and RAB38 in the mouse mimics Hermansky-Pudlak syndrome and critically impairs thrombosis

et al. 2019

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The biogenesis of lysosome related organelles is defective in Hermansky-Pudlak syndrome (HPS), a disorder characterized by oculocutaneous albinism and platelet dense granule (DG) defects. The first animal model of HPS was the fawn-hooded rat, harboring a spontaneous mutation inactivating the small guanosine triphosphatase Rab38. This leads to coat color dilution associated with the absence of DGs and lung morphological defects. Another RAB38 mutant, the cht mouse, has normal DGs, which has raised controversy about the role of RAB38 in DG biogenesis. We show here that murine and human, but not rat, platelets also express the closely related RAB32. To elucidate the parts played by RAB32 and RAB38 in the biogenesis of DGs in vivo and their effects on platelet functions, we generated mice inactivated for Rab32, Rab38, and both genes. Single Rab38 inactivation mimicked cht mice, whereas single Rab32 inactivation had no effect in DGs, coat color, or lung morphology. By contrast, Rab32/38 double inactivation mimicked severe HPS, with strong coat and eye pigment dilution, some enlarged lung multilamellar bodies associated with a decrease in the number of DGs. These organelles were morphologically abnormal, decreased in number, and devoid of 5-hydroxytryptamine content. In line with the storage pool defect, platelet activation was affected, resulting in severely impaired thrombus growth and prolongation of the bleeding time. Overall, our study demonstrates the absence of impact of RAB38 or RAB32 single deficiency in platelet biogenesis and function resulting from full redundancy, and characterized a new mouse model mimicking HPS devoid of DG content.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Combined deficiency of RAB32 and RAB38 in the mouse mimics Hermansky-Pudlak syndrome and critically impairs thrombosis

et al. 2019

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“…A specific mutation in the core component Vps33A, Vps33A Asp251Glu , gives rise to buff (bf) mice, which are a model for human Hermansky-Pudlak syndrome (HPS) (Suzuki et al, 2003). HPS is a multigenetic disorder characterized by defects in the biogenesis of two types of LROs: melanosomes and platelet-dense granules (El-Chemaly and Young, 2016). Other causative genes for HPS encode AP-3 subunits, which we discussed above in the context of Vps41 function.…”

Section: Mutations In Vps33a Cause Hermansky-pudlak Syndrome and Mucomentioning

confidence: 99%

“…Patients with HPS suffer from blood-clotting problems and have reduced pigmentation in the eyes, skin and hair (El-Chemaly and Young, 2016). This is reflected in the bf mice, which exhibit hypopigmentation and a mild platelet-storage pool deficiency.…”

Section: Mutations In Vps33a Cause Hermansky-pudlak Syndrome and Mucomentioning

confidence: 99%

CORVET, CHEVI and HOPS – multisubunit tethers of the endo-lysosomal system in health and disease

Beek

Jonker

Welle

et al. 2019

Journal of Cell Science

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Multisubunit tethering complexes (MTCs) are multitasking hubs that form a link between membrane fusion, organelle motility and signaling. CORVET, CHEVI and HOPS are MTCs of the endo-lysosomal system. They regulate the major membrane flows required for endocytosis, lysosome biogenesis, autophagy and phagocytosis. In addition, individual subunits control complex-independent transport of specific cargoes and exert functions beyond tethering, such as attachment to microtubules and SNARE activation. Mutations in CHEVI subunits lead to arthrogryposis, renal dysfunction and cholestasis (ARC) syndrome, while defects in CORVET and, particularly, HOPS are associated with neurodegeneration, pigmentation disorders, liver malfunction and various forms of cancer. Diseases and phenotypes, however, vary per affected subunit and a concise overview of MTC protein function and associated human pathologies is currently lacking. Here, we provide an integrated overview on the cellular functions and pathological defects associated with CORVET, CHEVI or HOPS proteins, both with regard to their complexes and as individual subunits. The combination of these data provides novel insights into how mutations in endo-lysosomal proteins lead to human pathologies.

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“…Hermansky-Pudlak syndrome is a heterogeneous and rare autosomal recessive genetic disorder (El-Chemaly & Young, 2016;Vicary et al, 2016). Patients with HPS-1, HPS-2, and HPS-4 tend to develop pulmonary fibrosis (Vicary et al, 2016).…”

Section: Variants In Hps-related Genesmentioning

confidence: 99%

Targeted resequencing reveals genetic risks in patients with sporadic idiopathic pulmonary fibrosis

Deng

Liu

et al. 2018

Human Mutation

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Idiopathic pulmonary fibrosis (IPF) is a genetic heterogeneous disease with high mortality and poor prognosis. However, a large fraction of genetic cause remains unexplained, especially in sporadic IPF (∼80% IPF). By systemically reviewing related literature and potential pathogenic pathways, 92 potentially IPF-related genes were selected and sequenced in genomic DNAs from 253 sporadic IPF patients and 125 matched health controls using targeted massively parallel next-generation sequencing. The identified risk variants were confirmed by Sanger sequencing. We identified two pathogenic and 10 loss-of-function (LOF) candidate variants, accounting for 4.74% (12 out of 253) of all the IPF cases. In burden tests, rare missense variants in three genes (CSF3R, DSP, and LAMA3) were identified that have a statistically significant relationship with IPF. Four common SNPs (rs3737002, rs2296160, rs1800470, and rs35705950) were observed to be statistically associated with increased risk of IPF. In the cumulative risk model, high risk subjects had 3.47-fold (95%CI: 2.07-5.81, P = 2.34 × 10 ) risk of developing IPF compared with low risk subjects. We drafted a comprehensive map of genetic risks (including both rare and common candidate variants) in patients with IPF, which could provide insights to help in understanding mechanisms, providing genetic diagnosis, and predicting risk for IPF.

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Hermansky-Pudlak Syndrome

Cited by 93 publications

References 41 publications

Combined deficiency of RAB32 and RAB38 in the mouse mimics Hermansky-Pudlak syndrome and critically impairs thrombosis

Combined deficiency of RAB32 and RAB38 in the mouse mimics Hermansky-Pudlak syndrome and critically impairs thrombosis

CORVET, CHEVI and HOPS – multisubunit tethers of the endo-lysosomal system in health and disease

Targeted resequencing reveals genetic risks in patients with sporadic idiopathic pulmonary fibrosis

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