AP3B1 – Hermansky-Pudlak Syndrome

AP3B1 encodes the beta3A subunit of the adaptor protein-3 (AP-3) complex, essential for intracellular vesicle formation from the trans-Golgi network to lysosome-related organelles. Loss-of-function variants in AP3B1 cause Hermansky-Pudlak syndrome type 2 (HPS-2), a subset of Hermansky-Pudlak syndrome characterized by oculocutaneous albinism, bleeding diathesis, and neutropenia. This autosomal recessive condition is clinically diagnosed by absent platelet dense bodies on electron microscopy and confirmed by biallelic pathogenic variants in AP3B1.

Genetic evidence includes 11 probands from five unrelated families with compound heterozygous or homozygous nonsense and frameshift alleles ([PMID:11809908]). Representative variants include c.1525C>T (p.Arg509Ter) and c.763C>T (p.Gln255Ter), both leading to absent AP3B1 mRNA and protein expression. Segregation is demonstrated by affected sib-pairs in multiplex families, with one additional affected relative confirmed via family studies.

A multicenter cohort of six children with genetically proven HPS-2 revealed early-onset pulmonary involvement, including ground-glass opacities and rapid fibrosing interstitial lung disease in childhood ([PMID:29580292]). Two independent case reports—a 13-year-old girl with periodontal manifestations ([PMID:35928686]) and a 2-year-old boy with skin lesions and epistaxis ([PMID:39171069])—expand the phenotypic spectrum to include severe periodontitis and mucocutaneous bleeding.

Functional studies show that AP3B1 deficiency abrogates assembly of the AP-3 heterotetramer, resulting in mislocalization of LAMP-3 and myeloperoxidase in patient fibroblasts and neutrophils. The absence of the beta3A subunit disrupts melanosome and platelet dense body biogenesis, accounting for hypopigmentation and storage pool deficiency. Mouse models of HPS-2 recapitulate neutropenia and fibrotic lung changes, supporting the pathogenic mechanism.

No conflicting evidence has been reported for AP3B1 in HPS-2. Integration of genetic and functional data establishes a definitive association between AP3B1 and Hermansky-Pudlak syndrome. Early genetic testing in patients with albinism, bleeding, and neutropenia facilitates diagnosis, guides surveillance for pulmonary fibrosis, and informs family planning.

Key take-home: Biallelic AP3B1 loss-of-function variants cause a definitive, autosomal recessive form of Hermansky-Pudlak syndrome with multi-organ involvement, supporting targeted genetic testing in suspected cases.

References

• Pediatric research • 2002 • Nonsense mutations in ADTB3A cause complete deficiency of the beta3A subunit of adaptor complex-3 and severe Hermansky-Pudlak syndrome type 2. PMID:11809908
• Orphanet journal of rare diseases • 2018 • Hermansky-Pudlak syndrome type 2 manifests with fibrosing lung disease early in childhood. PMID:29580292
• Frontiers in pediatrics • 2022 • Hermansky-Pudlak syndrome type 2: A rare cause of severe periodontitis in adolescents-A case study. PMID:35928686
• Cureus • 2024 • Hermansky-Pudlak Syndrome Type 2: A Case Report on an Ultra-Rare Disorder. PMID:39171069

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