Organization and Nucleotide Sequence of the Human Hermansky-Pudlak Syndrome (HPS) Gene

Bailin, Tu; Oh, Jangsuk; Feng, Guo; Fukai, Kazuyoshi; Spritz, Richard A.

doi:10.1111/1523-1747.ep12294634

Cited by 57 publications

(70 citation statements)

References 13 publications

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“…Primer pairs were designed for PCR amplification of each exon and their adjacent intron sequences of HPS human candidate genes (Table 1). Primer sequences are available upon request and have been previously described for HPS1 [49], AP3B1 [25], HPS3 [29], HPS4 [20], HPS5 [30] and HPS6 [32]. Standard PCR amplification procedures [48] were employed.…”

Section: Mutation Analysismentioning

confidence: 99%

An immunoblotting assay to facilitate the molecular diagnosis of Hermansky–Pudlak syndrome

Nazarian

Huizing

Helip-Wooley

et al. 2008

Molecular Genetics and Metabolism

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Hermansky-Pudlak syndrome (HPS) comprises a constellation of human autosomal recessive disorders characterized by albinism and platelet storage pool deficiency. At least eight types of HPS have been defined based on the identity of the mutated gene. These genes encode components of four ubiquitously expressed protein complexes, named Adaptor Protein (AP)-3 and Biogenesis of Lysosome-related Organelles Complex (BLOC)-1 through -3. In patients of Puerto Rican origin, the molecular diagnosis can be based on analysis of two founder mutations. On the other hand, identification of the HPS type in other patients relies on the sequencing of all candidate genes. In this work, we have developed a biochemical assay to minimize the number of candidate genes to be sequenced per patient. The assay consists of immunoblotting analysis of extracts prepared from skin fibroblasts, using antibodies to one subunit per protein complex. The assay allowed us to determine which complex was defective in each of a group of HPS patients with unknown genetic lesions, thus subsequent sequencing was limited to genes encoding the corresponding subunits. Because no mutations within the two genes encoding BLOC-3 subunits could be found in two patients displaying reduced BLOC-3 levels, the possible existence of additional subunits was considered. Through sizeexclusion chromatography and sedimentation velocity analysis, the native molecular mass of BLOC-3 was estimated to be 140 ± 30 kDa, a value most consistent with the idea that BLOC-3 is a HPS1•HPS4 heterodimer (∼156 kDa) albeit not inconsistent with the putative existence of a relatively small third subunit.

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Section: Mutation Analysismentioning

confidence: 99%

An immunoblotting assay to facilitate the molecular diagnosis of Hermansky–Pudlak syndrome

Nazarian

Huizing

Helip-Wooley

et al. 2008

Molecular Genetics and Metabolism

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“…The primers for PCR amplification of HPS1 were previously published [Bailin et al, 1997]. Primer sequences for BLOC1S2 and HPS6 are available upon request.…”

Section: Sequencing Of Hps1 Bloc1s2 and Hps6mentioning

confidence: 99%

A new genetic isolate with a unique phenotype of syndromic oculocutaneous albinism: clinical, molecular, and cellular characteristics

et al. 2006

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An extended, highly consanguineous Israeli Bedouin family with at least 20 individuals exhibiting a unique phenotype of oculocutaneous albinism (OCA) was identified. All known OCA genes were excluded in this family. Electron microscopic analysis of platelets revealed absence of dense bodies, suggesting a diagnosis of Hermansky-Pudlak syndrome (HPS). HPS is a rare autosomal recessive disorder of lysosome-related organelle biogenesis, clinically characterized by OCA and platelet dysfunction, sometimes accompanied by other systemic pathologies. All human HPS genes (HPS1-8) and five genes corresponding to murine HPS models were evaluated. Haplotype analysis and homozygosity mapping of the HPS loci revealed linkage to chromosome 10 in the studied family. Subsequently, a novel insertion mutation, c.1066-1067insG was identified in HPS6. Most frameshift mutations generating premature termination codon cause mRNA nonsense mediated decay (NMD), while intronless genes like HPS6 are usually not monitored by NMD. Expression analysis revealed no mRNA decay in patient's fibroblasts, hence truncated protein is most probably produced. Confocal microscopy revealed abnormal distribution of LAMP-3 (lysosomal associated membrane protein-3) in fibroblasts from the patients, indicating abnormal trafficking of lysosomal lineage organelles. So far, a single HPS-6 patient phenotypically similar to HPS-3 and HPS-5 has been identified. The HPS-6 phenotype in the studied family is unique since it resembles OCA and not HPS. Therefore, our finding broadens the phenotypic definition of HPS. Two major genetic isolates of HPS-1 and HPS-3 patients were previously diagnosed in Puerto Rico. The extended Bedouin family is the largest isolate of non-Puerto Rican HPS patients.

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“…time was prolonged to 10 min, there was no abnormality in the number of platelets or coagulation factors, suggesting a storage pool deficiency. We then screened for mutations in his HPS1 gene with the PCR-SSCP/heteroduplex method [7] using the primers and PCR conditions described by Bailin et al [8]. Direct sequencing of an aberrant band found with the SSCP screening method finally detected a homozygous splice site mutation, IVS5 +5G !…”

mentioning

confidence: 99%

Investigation on the IVS5 +5G → A splice site mutation of HPS1 gene found in Japanese patients with Hermansky–Pudlak syndrome

Suzuki

Ito

Inagaki

et al. 2004

Journal of Dermatological Science

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Organization and Nucleotide Sequence of the Human Hermansky-Pudlak Syndrome (HPS) Gene

Cited by 57 publications

References 13 publications

An immunoblotting assay to facilitate the molecular diagnosis of Hermansky–Pudlak syndrome

An immunoblotting assay to facilitate the molecular diagnosis of Hermansky–Pudlak syndrome

A new genetic isolate with a unique phenotype of syndromic oculocutaneous albinism: clinical, molecular, and cellular characteristics

Investigation on the IVS5 +5G → A splice site mutation of HPS1 gene found in Japanese patients with Hermansky–Pudlak syndrome

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