HPS5 – Hermansky-Pudlak syndrome

Hermansky-Pudlak syndrome (HPS) is an autosomal recessive disorder characterized by oculocutaneous albinism, bleeding diathesis, and potential pulmonary complications. Mutations in HPS5 (HGNC:17022) have been repeatedly identified in affected individuals with Hermansky-Pudlak syndrome (MONDO:0019312), establishing a strong clinical association through multiple case reports and multi‐patient studies (PMID:29090612).

Several case reports have documented patients harboring homozygous or compound heterozygous mutations in HPS5. In one notable study, a 65-year-old patient with subtle oculocutaneous hypopigmentation and mild bleeding diathesis was found to carry a novel homozygous mutation, specifically c.1960A>T (p.Lys654Ter) (PMID:29090612). This variant, alongside others reported in different cohorts, underscores the recurrent disruption of HPS5 function in affected probands.

Multi-patient investigations further reinforce this association. In a study characterizing the cellular, molecular, and clinical features of HPS5 subtype patients, several novel mutations were identified across unrelated individuals, with supportive segregation data observed in family studies (PMID:15296495). The collective genetic evidence, including over 11 probands from independent cohorts, confirms the critical role of HPS5 in the pathogenesis of Hermansky-Pudlak syndrome.

Functional analyses have provided important mechanistic insights into HPS5 pathogenicity. Experimental models, including zebrafish and cellular systems, demonstrate that HPS5 mutations lead to defective melanocyte differentiation and impaired biogenesis of lysosome-related organelles. These assays, supported by evidence of altered intracellular vesicle trafficking and melanosome formation, parallel the human phenotype and substantiate the molecular diagnosis (PMID:23893484; PMID:28296950).

Although explicit counts of segregating affected relatives are not uniformly provided across studies, the convergence of independent genetic findings in multiple families and the recurrent identification of pathogenic variants offer strong support for the disease association. These observations have direct implications for diagnostic decision-making, highlighting the importance of incorporating both genetic screening and functional analyses in clinical evaluations.

In summary, the integration of extensive genetic evidence with robust functional data supports a strong association between HPS5 mutations and Hermansky-Pudlak syndrome. This evidence not only aids precise diagnosis but also informs prognosis and clinical management, emphasizing the clinical utility of comprehensive molecular testing in rare genetic disorders.

References

• Platelets • 2018 • Hermansky-Pudlak syndrome subtype 5 novel mutation in a 65 year-old with oculocutaneous hypopigmentation and mild bleeding diathesis: The importance of recognizing a subtle phenotype PMID:29090612
• Traffic • 2004 • Cellular, molecular and clinical characterization of patients with Hermansky-Pudlak syndrome type 5 PMID:15296495
• Genetics • 2013 • snow white, a zebrafish model of Hermansky-Pudlak Syndrome type 5 PMID:23893484
• PloS one • 2017 • Cellular and molecular defects in a patient with Hermansky-Pudlak syndrome type 5 PMID:28296950

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