Positional cloning of a gene for Hermansky–Pudlak syndrome, a disorder of cytoplasmic organelles

Oh, Jangsuk; Bailin, Tu; Fukai, Kazuyoshi; Feng, Guo; Ho, Lingling; Mao, Jen-i; Frenk, E.; Tamura, Naoaki; Spritz, Richard A.

doi:10.1038/ng1196-300

Cited by 280 publications

(357 citation statements)

References 21 publications

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“…Another 25% of HPS cases on the island occur from a deletion (3,904 base pairs) in HPS3. HPS3 is believed to have developed in the 1880s-1890s in the central mountainous region of Puerto Rico (9,17,19). Consistent with the genetic drift expected over hundreds of years, more recent studies have suggested that carrier frequencies for HPS1 and HPS3 are similar across Puerto Rico (9,20).…”

Section: Genetic and Functional Abnormalitiesmentioning

confidence: 88%

Pulmonary Fibrosis in Hermansky-Pudlak Syndrome

et al. 2016

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Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive genetic disorder characterized by oculocutaneous albinism and a bleeding diathesis due to platelet dysfunction. More than 50% of cases worldwide are diagnosed on the Caribbean island of Puerto Rico. Genetic testing plays a growing role in diagnosis; however, not all patients with HPS have identified genetic mutations. In Puerto Rico, patients with HPS are often identified shortly after birth by their albinism, although the degree of hypopigmentation is highly variable. Ten subtypes have been described. Patients with HPS-1, HPS-2, and HPS-4 tend to develop pulmonary fibrosis in Puerto Rico; 100% of patients with HPS-1 develop HPS-PF. HPS-PF and idiopathic pulmonary fibrosis are considered similar entities (albeit with distinct causes) because both can show similar histological disease patterns. However, in contrast to idiopathic pulmonary fibrosis, HPS-PF manifests much earlier, often at 30-40 years of age. The progression of HPS-PF is characterized by the development of dyspnea and increasingly debilitating hypoxemia. No therapeutic interventions are currently approved by the U.S. Food and Drug Administration for the treatment of HPS and HPS-PF. However, the approval of two new antifibrotic drugs, pirfenidone and nintedanib, has prompted new interest in identifying drugs capable of reversing or halting the progression of HPS-PF. Thus, lung transplantation remains the only potentially life-prolonging treatment. At present, two clinical trials are recruiting patients with HPS-PF to identify biomarkers for disease progression. Advances in the diagnosis and management of these patients will require the establishment of multidisciplinary centers of excellence staffed by experts in this disease.

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Section: Genetic and Functional Abnormalitiesmentioning

confidence: 88%

Pulmonary Fibrosis in Hermansky-Pudlak Syndrome

et al. 2016

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“…13 17 ) result from mutations in genes that encode both known vesicle trafficking proteins and novel proteins. In the mouse, seven additional genes 4,5,9,18-21 associated with HPS have been identified.…”

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confidence: 99%

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

et al. 2003

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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 [1][2][3] . In mice, at least 16 loci are associated with HPS 4-6 , 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 α-and β-dystrobrevins, components of the dystrophin-associated protein complex (DPC) in both muscle and nonmuscle cells 8 . We also show that dysbindin is a component of the biogenesis of lysosome-related organelles complex 1 ), which regulates Correspondence should be addressed to R.T.S (richard.swank@roswellpark.org). 11 These authors contributed equally to this work.Note: Supplementary information is available on the Nature Genetics website. Competing Interests Statement:The authors declare that they have no competing financial interests. We previously showed 7 that the sdy mutant mouse is a valid model for human HPS and localized the gene sdy to mouse chromosome 13. Here we genotyped 20 microsatellite markers in 1,250 progeny of sdy backcrosses to localize sdy to the 2.2-cM interval between D13Mit244 and D13Mit267 (Fig. 1). We identified the sdy interval within a 28-Mb scaffold (Celera Discovery System) containing two known genes, Jmj and Dtnbp1 (Fig. 1b). We used PCR products of D13Mit179 and the Dtnbp1 cDNA as probes to generate a BAC contig covering the sdy interval (Fig. 1b). NIH Public AccessNorthern-blot analysis and sequencing of RT-PCR products of Jmj identified no abnormalities in sdy mutants, but truncated genomic PCR products (Fig. 2a) and mRNA ( Fig. 2b) of Dtnbp1 were apparent in sdy tissues. Sequencing of RT-PCR products showed that exons 6 and 7 (156 bp) of Dtnbp1 were deleted in mutant mice, resulting in the loss of 52 amino acids from position 119-172 of the dysbindin protein ( Supplementary Fig. 1 online). Genomic sequencing showed that this results from a large deletion (38,129 bp) from nucleotide 3,701 of intron 5 to nucleotide 12,377 of intron 7. This deletion was not found in twelve other inbred mouse strains (Fig. 2a), including coisogenic DBA/2J, indicating that it was not a strain-specific polymorphism. This in-frame deletion creates a 1.5-kb mutant dysbindin transcript ( Fig. 2b) and abolishes expression of the 51-kDa dysbindin 8 protein in sdy/sdy mice ( Fig. 2c). Expression of dysbindin is restored in sdy/sdy transgenic mice containing BAC54F9 (Fig. 2c). Platelet serotonin levels of six of these transgenics were normal (>1.12 μg per 10 9 platelets), whereas all five sdy/sdy litter-mates without BAC54F9 had platelet serotonin levels of <0.06 μg per 10 9 platelets. sdy/sdy progeny containing the BAC transgene had dar...

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“…The relatively small genetic interval defined by these studies contained no apparent candidate genes for the disorder, but corresponded to a small enough physical interval to permit a 'positional cloning' approach to identify the HPS gene (32). Once identified, the HPS gene was found to span 30.5 kb of DNA and consist of 20 exons, the first two of which are entirely noncoding (33).…”

Section: The Hps Gene and Mutationsmentioning

confidence: 99%

“…No HPS mRNA is detectable from this mutant allele (39), indicating that HPS mRNA is subject to the so-called 'nonsense-mediated decay' of aberrantly-translated mRNAs. Most Puerto Rican HPS patients are homozygous for the codon 491-496 duplication (32,35,39), although HPS has not been reported elsewhere in the Caribbean, suggesting that this HPS gene mutant allele probably arose on or was introduced to the island of Puerto Rico early during its history and became frequent by chance and occult inbreeding; there is no evidence for any selective Pigment Cell Res. 13,2000 As shown in Table 1, mutations in a number of the other mouse HPS-like loci have also been found.…”

Section: The Hps Gene and Mutationsmentioning

confidence: 99%

“…Two major HPS mRNA isoforms, resulting from alternative splicing of exon 9 which encodes amino acids 290-313, are coordinately expressed in many or all tissues and cell types and encode major and minor HPS protein isoforms of 79.3 and 75.9 kDa, respectively (33,34). A number of other minor alternatively spliced or polyadenylated HPS transcripts have also been identified (32,34), but it seems unlikely they are of biological importance.…”

Section: The Hps Gene and Mutationsmentioning

confidence: 99%

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Hermansky–Pudlak Syndrome and Pale Ear: Melanosome‐Making for the Millennium

Spritz

2000

Pigment Cell Research

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Hermansky-Pudlak syndrome (HPS) is a rare autosomalweight complex involved in the biogenesis of early melarecessive disorder characterized principally by oculocutaneous nosomes. Additional disorders with similarities to HPS have been identified in man, mouse, flies, and yeast, and it is rapidly albinism, a bleeding tendency, and a ceroid-lipofuscin lysosomal storage disease. These clinical manifestations of HPS are becoming clear that understanding these disorders will shed new light on the mechanisms by which cells traffic newly associated with defects of multiple cytoplasmic organellesmelanosomes, platelet granules, and lysosomes -suggesting synthesized proteins through the cytoplasm to assemble functional organelles. that the HPS gene product is involved in some shared feature of the biogenesis or functions of these diverse organelles. The HPS gene has been cloned, and a number of pathologic

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Positional cloning of a gene for Hermansky–Pudlak syndrome, a disorder of cytoplasmic organelles

Cited by 280 publications

References 21 publications

Pulmonary Fibrosis in Hermansky-Pudlak Syndrome

Pulmonary Fibrosis in Hermansky-Pudlak Syndrome

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 and Pale Ear: Melanosome‐Making for the Millennium

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