HPS1 – Hermansky-Pudlak Syndrome

Hermansky-Pudlak syndrome (HPS) is an autosomal recessive disorder defined by oculocutaneous albinism and a bleeding diathesis, often accompanied by pulmonary fibrosis and granulomatous colitis. HPS type 1 is caused by biallelic mutations in HPS1, which encodes a cytosolic protein that associates with membranes to regulate lysosome-related organelle biogenesis. Genetic studies have identified over 300 unrelated HPS1-mutant patients, including a 16-bp founder duplication (c.1472_1487dup (p.His497fs)) in northwest Puerto Rico and recurrent splice-site and frameshift alleles in Japanese and Spanish cohorts ([PMID:9787100]; [PMID:10971344]; [PMID:12442288]).

1. Clinical Validity

The HPS1–Hermansky-Pudlak syndrome association is Definitive. More than 300 probands from diverse ethnicities have been reported with biallelic loss-of-function HPS1 variants, including founder and private alleles, confirmed by segregation and consistent phenotype ([PMID:9787100]). Functional concordance between human disease, mouse “pale ear” models, and medaka fish mutants further substantiates causality.

2. Genetic Evidence

Inheritance is autosomal recessive. Over 60 distinct LoF variants (nonsense, frameshift, splice-site) have been described in >300 probands. The most common HPS1 allele in Puerto Rico is c.1472_1487dup (p.His497fs) ([PMID:12442288]). Case reports include a Japanese man compound heterozygous for c.962dup (p.Thr322fs) and c.398+5G>A ([PMID:10971344]), and a Spanish family with a de novo nonsense allele Arg-131Ter ([PMID:14510955]) segregating in two asymptomatic heterozygous relatives. Segregation of HPS1 mutations with disease in multiple families and compound heterozygosity in probands supports a Strong genetic evidence score.

3. Functional / Experimental Evidence

Biochemical assays show that HPS1p is a predominantly cytosolic 80 kDa protein that associates with membranes independently of AP-3, implicating a unique BLOC-3 function ([PMID:10625677]). Cryo-EM of the HPS1–HPS4 BLOC-3 complex defines interaction domains critical for melanosome and platelet dense-granule biogenesis, and zebrafish and mouse models recapitulate hypopigmentation and bleeding phenotypes ([PMID:40140412]). Functional evidence is Moderate.

4. Conflicting Evidence

Heterozygous carriers may show subclinical platelet ultrastructural abnormalities without overt bleeding, but no refuting studies have challenged biallelic HPS1 pathogenicity.

5. Integration & Take-Home

Biallelic HPS1 loss-of-function variants cause a coherent syndrome of albinism, bleeding diathesis, colitis, and pulmonary fibrosis by disrupting lysosome-related organelle formation. Early genetic testing for HPS1 enables prompt diagnosis, subtype-specific surveillance for pulmonary fibrosis, and informed family planning.

Key Take-Home: HPS1 mutational analysis is essential for diagnosis and management of Hermansky-Pudlak syndrome type 1, informing prognosis and guiding multidisciplinary care.

References

• Molecular genetics and metabolism • 1998 • Hermansky-Pudlak syndrome: models for intracellular vesicle formation PMID:9787100
• The British journal of dermatology • 2000 • Heterozygous HPS1 mutations in a case of Hermansky-Pudlak syndrome with giant melanosomes PMID:10971344
• Human mutation • 2002 • Hermansky-Pudlak syndrome type 1: gene organization, novel mutations, and clinical-molecular review of non-Puerto Rican cases PMID:12442288
• The Journal of biological chemistry • 2000 • Molecular characterization of the protein encoded by the Hermansky-Pudlak syndrome type 1 gene PMID:10625677
• Nature communications • 2025 • Cryo-EM structure of the BLOC-3 complex provides insights into the pathogenesis of Hermansky-Pudlak syndrome PMID:40140412

Evidence Based Scoring (AI generated)