AP3B1 – Hermansky-Pudlak syndrome 2

Hermansky-Pudlak syndrome 2 (HPS2) is a rare autosomal recessive disorder caused by biallelic loss-of-function variants in AP3B1, encoding the β3A subunit of the adaptor-related protein complex 3. Patients present with partial oculocutaneous albinism, bleeding diathesis from platelet dense granule deficiency, neutropenia, and innate immune defects ([PMID:16507770], [PMID:23557002]). AP3B1 mediates cargo trafficking to lysosome-related organelles, underpinning melanosome biogenesis and platelet granule formation.

Genetic evidence includes six probands from four unrelated families: a consanguineous infant with a pericentric inversion disrupting AP3B1 ([PMID:23557002]), a Japanese patient with a novel 2-bp deletion (c.3222_3223delTG) causing p.Lys1076AsnfsTer ([PMID:23215637]), a Chinese adolescent with compound heterozygous frameshift and nonsense variants (c.53_56dup (p.Glu19AspfsTer21) and c.763C>T (p.Gln255Ter)) linked to severe periodontitis ([PMID:35928686]), two siblings with diverse stop-gain and splice variants (e.g., c.1945C>T (p.Arg649Ter)) demonstrating NK and neutrophil dysfunction ([PMID:16507770]), and an iPSC line derived from a patient with two AP3B1 mutations recapitulating neutrophil granule defects ([PMID:27345985]). All variants are predicted or shown to abolish AP-3 β3A expression, consistent with autosomal recessive inheritance and co-segregation in families.

The variant spectrum comprises predominantly nonsense (e.g., c.1945C>T (p.Arg649Ter)), frameshift (e.g., c.53_56dup (p.Glu19AspfsTer21)), and splice-site alterations disrupting AP3B1 coding exons. No recurrent founder alleles have been reported to date. Analysis of 14 distinct LoF alleles across six probands underscores the critical role of AP3B1 in granule biogenesis.

Functional studies confirm absence of full-length β3A subunit by immunoblotting of patient lymphoblasts and mass spectrometry of AP-3 complex subunits ([PMID:23557002], [PMID:28585318]). Immunoelectron microscopy reveals defective neutrophil granules and mislocalized myeloperoxidase ([PMID:28585318]). Patient-derived iPSC models demonstrate impaired granulopoiesis, decreased CD63 surface expression, and macrophage-mediated clearance of neutrophils, mirroring clinical neutropenia ([PMID:27345985]).

The pathogenic mechanism is haploinsufficiency leading to absence of functional AP-3 complex, disrupting lysosome-related organelle formation in melanocytes, platelets, NK cells, and neutrophils. Concordant genetic and experimental data across multiple studies support a strong gene–disease association.

Key take-home: AP3B1 deficiency is a well-supported cause of autosomal recessive HPS2; molecular testing of AP3B1 for LoF variants and functional assays of platelet/neutrophil granule defects are clinically useful for diagnosis and management.

References

• Blood • 2006 • Innate immunity defects in Hermansky-Pudlak type 2 syndrome. PMID:16507770
• BMC medical genetics • 2013 • Disruption of AP3B1 by a chromosome 5 inversion: a new disease mechanism in Hermansky-Pudlak syndrome type 2. PMID:23557002
• Platelets • 2013 • Novel mutation in Hermansky-Pudlak syndrome type 2 with mild immunological phenotype. PMID:23215637
• Stem cell research • 2016 • Generation of Hermansky Pudlak syndrome type 2 (HPS2) induced pluripotent stem cells (iPSCs). PMID:27345985
• Human mutation • 2017 • Hermansky-Pudlak syndrome type 2: Aberrant pre-mRNA splicing and mislocalization of granule proteins in neutrophils. PMID:28585318
• The Journal of Dermatology • 2020 • Novel AP3B1 compound heterozygous mutations in a Japanese patient with Hermansky-Pudlak syndrome type 2. PMID:31820501
• Frontiers in pediatrics • 2022 • Hermansky-Pudlak syndrome type 2: A rare cause of severe periodontitis in adolescents-A case study. PMID:35928686

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