AP3B1 was first reported in relation to autosomal recessive Hermansky-Pudlak syndrome 2 in 1999 (Dell'Angelica et al., PMID 10024875). Hermansky-Pudlak syndrome 2 is a subtype of HPS, characterized by neutropenia and immune defects, in addition to oculocutaneous albinism and bleeding tendency. In some individuals, pulmonary fibrosis and granulomatous colitis are also observed. AP3B1 encodes the β1 subunit of adaptor complex-3, AP3, which is a coat protein complex that forms intracellular vesicles (Huizing et al., Hermansky-Pudlak Syndrome, GeneReviews). This complex is expressed ubiquitously. In the neurological tissues, however, the β2 subunit encoded by AP3B2 replaces β1 in the AP3 complex. At least 28 nonsense, frameshift and missense variants have been reported in humans (PMID: 28585318). Evidence supporting this gene-disease relationship includes case-level data and experimental data.
Summary of Case Level Data: 12 POINTS Variants in this gene have been reported in at least 9 probands in 8 publications (PMIDs 28585318, 16537806, 19679886, 23215637, 10024875, 14566336, 16551969, 11809908) Variants in this gene segregated with disease in 3 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached.
The mechanism for disease is homozygous loss of function (Huizing et al., Hermansky-Pudlak Syndrome, GeneReviews).
Summary of Experimental Data: 4 POINTS This gene-disease association is supported by animal models and in vitro functional assays. The ‘Pearl’ mouse model is a spontaneously mutated mouse that expresses the HPS2 phenotype (PMID: 9931340). Yang et al., generated homozygous AP3B1 knock-out mice that showed similar phenotypes as that seen in HPS2 patients (PMID: 11058094). In-vitro studies in patient-derived cells and transfected cultures show defective intracellular protein trafficking in AP3B1 mutants (PMIDs 30630984, 11452004, 14566336, 10024875). In summary, AP3B1 is definitively associated with autosomal recessive Hermansky-Pudlak syndrome 2. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Hemostasis/Thrombosis gene curation expert panel on 2/26/20 (SOP Version 6).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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