Identification and clinical characterization of Hermansky–Pudlak syndrome alleles in the Pakistani population

Yousaf, Sairah; Shahzad, Mohsin; Kausar, Tasleem; Sheikh, Shakeel A.; Tariq, Nabeela; Shabbir, Asra S; Ali, Muhammad; Waryah, Ali Muhammad; Shaikh, Rehan Sadiq; Riazuddin, Saima; Ahmed, Zubair M.

doi:10.1111/pcmr.12438

Cited by 18 publications

(27 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This boy’s manifestations of disease resemble those reported in most patients with BLOC-1-related HPS types. Including our case, 3, 7 and 3 patients are reported to have HPS-7, HPS-8 and HPS-9, respectively [2, 10–15]. Compared to patients with the more common HPS-1 type, the relatively mild pigmentation defect and tendency to bleed may contribute to missed diagnoses and underreporting of patients with these unusual genetic types.…”

Section: 1 Discussionmentioning

confidence: 81%

See 1 more Smart Citation

Clinical and molecular phenotyping of a child with Hermansky-Pudlak syndrome-7, an uncommon genetic type of HPS

Bryan

Tolman

Simon

et al. 2017

Molecular Genetics and Metabolism

View full text Add to dashboard Cite

Purpose Hermansky-Pudlak syndrome (HPS) is a rare inherited disorder with ten reported genetic types; each type has defects in subunits of either Adaptor Protein-3 complex or Biogenesis of Lysosome-related Organelles Complex (BLOC)-1, -2, or -3. Very few patients with BLOC-1 deficiency (HPS-7, -8, and -9 types) have been diagnosed. We report results of comprehensive clinical testing and molecular analyses of primary fibroblasts from a new case of HPS-7. Results A 6-year old Paraguayan male presented with hypopigmentation, ocular albinism, nystagmus, reduced visual acuity, and easy bruising. He also experienced delayed motor and language development as a very young child; head and chest trauma resulted in intracranial hemorrhage with subsequent right hemiparesis and lung scarring. There was no clinical evidence of immunodeficiency or colitis. Whole mount transmission electron microscopy revealed absent platelet delta granules; platelet aggregation testing was abnormal. Exome sequencing revealed a homozygous nonsense mutation in the Dystrobrevin binding protein 1 (DTNBP1) gene [NM 032122.4: c.307C>T; p.Gln103*], previously reported in a Portuguese adult. The gene encodes the dysbindin subunit of BLOC-1. Dysbindin protein expression was negligible in our patient’s dermal fibroblasts, while his DTNBP1 mRNA level was similar to that of a normal control. Conclusions Comprehensive clinical evaluation of the first pediatric case reported with HPS-7 reveals oculocutaneous albinism and platelet storage pool deficiency; his phenotype is consistent with findings in other patients with BLOC-1 disorders. This patient’s markedly reduced Dysbindin protein expression in HPS-7 resulted from a mechanism other than nonsense mediated decay.

show abstract

Section: 1 Discussionmentioning

confidence: 81%

“…Patients with BLOC-1 disorders present with various clinical manifestations. Pulmonary fibrosis has not been described in the 12 other published cases with a BLOC-1 disease; only one patient had recurrent cutaneous infections [2, 10–15]. Two adult patients with HPS-7 have been reported [10, 13].…”

Section: 1 Introductionmentioning

confidence: 99%

Clinical and molecular phenotyping of a child with Hermansky-Pudlak syndrome-7, an uncommon genetic type of HPS

Bryan

Tolman

Simon

et al. 2017

Molecular Genetics and Metabolism

View full text Add to dashboard Cite

show abstract

“…HPS affects approximately 500,000 to 1,000,000 people worldwide, and has been reported in individuals from India, Japan, China, the United Kingdom, Western Europe, Pakistan, Canada, and the United States (7,8). The international HPS Network registry also includes patients from Israel, Australia, Hungary, Mexico, Brazil, Peru, Qatar, and Bolivia, among others.…”

mentioning

confidence: 99%

Pulmonary Fibrosis in Hermansky-Pudlak Syndrome

et al. 2016

View full text Add to dashboard Cite

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.

show abstract

“… f NC_000010.11:g.10:98435762‐98435882 (GRCh38): Genomic 121‐bp deletion, including a part of intron 3 and exon 4 (Yousaf et al, 2016). …”

Section: Introductionmentioning

confidence: 99%

Hermansky–Pudlak syndrome: Mutation update

et al. 2020

View full text Add to dashboard Cite

Hermansky-Pudlak syndrome (HPS) is a group of 10 autosomal recessive multisystem disorders, each defined by the deficiency of a specific gene. HPS-associated genes encode components of four ubiquitously expressed protein complexes: Adaptor protein-3 (AP-3) and biogenesis of lysosome-related organelles complex-1 (BLOC-1) through -3. All individuals with HPS exhibit albinism and a bleeding diathesis; additional features occur depending on the defective protein complex. Pulmonary fibrosis is associated with AP-3 and BLOC-3 deficiency, immunodeficiency with AP-3 defects, and gastrointestinal symptoms are more prevalent and severe in BLOC-3 deficiency. Therefore, identification of the HPS subtype is valuable for prognosis, clinical management, and treatment options. The prevalence of HPS is estimated at 1-9 per 1,000,000. Here we summarize 264 reported and novel variants in 10 HPS genes and estimate that~333 Puerto Rican HPS subjects and~385 with other ethnicities are reported to date. We provide pathogenicity predictions for missense and splice site variants and list variants with high minor allele frequencies. Current cellular and clinical aspects of HPS are also summarized. This review can serve as a manifest for molecular diagnostics and genetic counseling aspects of HPS.

show abstract

Identification and clinical characterization of Hermansky–Pudlak syndrome alleles in the Pakistani population

Cited by 18 publications

References 14 publications

Clinical and molecular phenotyping of a child with Hermansky-Pudlak syndrome-7, an uncommon genetic type of HPS

Clinical and molecular phenotyping of a child with Hermansky-Pudlak syndrome-7, an uncommon genetic type of HPS

Pulmonary Fibrosis in Hermansky-Pudlak Syndrome

Hermansky–Pudlak syndrome: Mutation update

Contact Info

Product

Resources

About