Alternative titles; symbols
HGNC Approved Gene Symbol: AP3B1
Cytogenetic location: 5q14.1 Genomic coordinates (GRCh38) : 5:78,000,522-78,294,698 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q14.1 | Hermansky-Pudlak syndrome 2 | 608233 | Autosomal recessive | 3 |
The AP3B1 gene encodes the large B1 subunit of the adaptor-related protein complex-3, a heterotetrameric complex involved in protein trafficking to lysosomes or specialized endosomal-lysosomal organelles such as pigment granules, melanosomes, and platelet dense granules (Dell'Angelica et al., 1998).
Dell'Angelica et al. (1997) cloned a cDNA encoding the 140-kD subunit of AP3, named beta-3A-adaptin, by its homology to beta-NAP (602166). The 1,094-amino acid beta-3A-adaptin protein shares 61% identity with beta-NAP and is also related to the beta-1- (AP1B1; 600157) and beta-2-adaptin (AP2B1; 601025) subunits of complexes AP1 and AP2, respectively. The central hydrophilic region of beta-3A-adaptin is rich in acidic and serine residues and contains many potential sites for phosphorylation; the authors demonstrated that beta-3A-adaptin is phosphorylated in vivo on serine residues. Northern blot analysis detected an approximately 4.2-kb transcript in all human tissues examined and in nonneuronal and neuronal cell lines.
Independently, Simpson et al. (1997) cloned a beta-3A-adaptin cDNA which encodes a 1,093-amino acid protein.
Huizing et al. (2002) determined that the AP3B1 gene contains 27 exons.
Stumpf (2024) mapped the AP3B1 gene to chromosome 5q14.1 based on an alignment of the AP3B1 sequence (GenBank BC038444) with the genomic sequence (GRCh38).
Dell'Angelica et al. (1998) demonstrated that mammalian AP3 adaptor complex associated with clathrin by interaction of the appendage domain of the AP3B1 protein with the amino-terminal domain of the clathrin heavy chain (CLTC; 118955).
Sasai et al. (2010) identified adaptor protein-3 as the protein complex responsible for the trafficking of Toll-like receptor-9 (TLR9; 605474) from endosomes to a specialized lysosome-related organelle. This trafficking is required for the activation of type I IFN (147660) by TLR9. Sasai et al. (2010) concluded that their results revealed an intracellular mechanism for bifurcation of TLR9 signals by selective receptor trafficking within the endosomal system.
In 2 patients with Hermansky-Pudlak syndrome-2 (HPS2; 608233), Dell'Angelica et al. (1999) identified mutations in the AP3B1 gene (603401.0001-603401.0002). The patients' fibroblasts exhibited drastically reduced levels of AP3 due to enhanced degradation of mutant beta-3A. The AP3 deficiency resulted in increased surface expression of the lysosomal membrane proteins CD63 (155740), LAMP1 (153330), and LAMP2 (309060), but not of nonlysosomal proteins. These differential effects are consistent with the preferential interaction of the AP3 mu-3A subunit with tyrosine-based signals involved in lysosomal targeting. Dell'Angelica et al. (1999) suggested that AP3 functions in protein sorting to lysosomes and that HPS provides an example of a human disease in which altered trafficking of integral membrane proteins is due to mutations in a component of the sorting machinery.
Clark et al. (2003) found that CD8 (see 186910)-positive cytotoxic T lymphocytes (CTLs) from an immunodeficient HPS patient lacked the beta-3A, gamma, and mu-3A subunits of AP3, consistent with HPS2. By PCR analysis, they identified compound heterozygosity for mutations in the AP3B1 gene. Clark et al. (2003) determined that AP3 deficiency results in loss of microtubule-mediated movement of enlarged perforin- and granzyme-containing lytic granules toward the immunologic synapse and a profound loss of CTL-mediated killing.
The autosomal recessive mouse mutation 'pearl' (pe) maps to distal mouse chromosome 13. Pearl mice have been thought to be appropriate models for HPS because they exhibit hypopigmentation, lysosomal secretion abnormalities, and platelet-dense granules with reduced levels of adenine nucleotides and serotonin. The changes in platelets lead to prolonged bleeding. Additionally, pearl mice exhibit reduced sensitivity in the dark-adapted state, suggesting a model for human congenital stationary night blindness (Balkema et al., 1983). The adaptor-related coat complex, termed AP3, likely facilitates trafficking of vesicles from the trans-Golgi network and/or endosomal compartments by interacting with tyrosine and dileucine signals on proteins of lysosomes and other intracellular organelles. AP3 is heterotetrameric, containing 2 large subunits, delta- and beta-3, a medium-sized subunit, mu-3, and a small subunit, sigma-3. Feng et al. (1999) reported positional/candidate cloning of the pearl gene and presented evidence from mutation analysis that the primary pearl gene defect is in the Ap3b1 gene, which encodes the beta-3A subunit of the AP3 adaptor complex. Mutations in 2 different pearl alleles, including a large internal tandem duplication and a deletion, were predicted to abrogate function of the beta-3A protein. Significantly lowered expression of altered beta-3A transcripts occurred in kidney of both mutant alleles. Dell'Angelica et al. (1999) identified a mutant beta-3A subunit of AP3 in 2 brothers with HPS, supporting the proposal that the pearl mutation of mice is a model for HPS.
Zhen et al. (1999) found that the beta-3A subunit was undetectable in all cells and tissues of the pearl mouse. In addition, expression of other subunit proteins of the AP3 complex was decreased. The subcellular distribution of the remaining AP3 subunits in platelets, macrophages, and a melanocyte-derived cell line of pearl mice was changed from the normal punctate, probably endosomal, pattern to a diffuse cytoplasmic pattern. Ultrastructural abnormalities in mutant lysosomes were likewise apparent in mutant kidney and a cultured mutant cell line. Five other mouse models of Hermansky-Pudlak syndrome were found to have normal expression of AP3 subunits, indicating genetic heterogeneity comparable to that found in the human. In contrast, another mouse HPS-like mutant, mocha, contains mutations in the delta subunit of the AP3 complex (AP3D1; 607246) together with decreased expression of the other AP3 complex proteins.
To test for in vivo interactions between the HPS1 and HPS2 genes in the production and function of intracellular organelles, Feng et al. (2002) created mice doubly heterozygous for the 2 mutant genes by appropriate breeding. Cooperation between the 2 genes in melanosome production was evident in increased hypopigmentation of the coat together with dramatic quantitative and qualitative alterations of melanosomes of the retinal pigment epithelium and choroid of double-mutant mice. Lysosomal and platelet dense granule abnormalities, including hyposecretion of lysosomal enzymes from kidneys and depression of serotonin concentrations of platelet dense granules were likewise more severe in double than in single mutants. Also, lysosomal enzyme concentrations were significantly increased in lungs of double-mutant mice. Interaction between the 2 genes was specific in that effects on organelles were confined to melanosomes, lysosomes, and platelet dense granules. Together, the evidence indicated that these 2 HPS genes function largely independently at the whole-organism level to affect the production and function of all 3 organelles. Furthermore, the increased lysosomal enzyme levels in lung of double-mutant mice suggested a cause of a major clinical problem of Hermansky-Pudlak syndrome, lung fibrosis.
Cyclic hematopoiesis is a stem cell disease in which the number of neutrophils and other blood cells oscillates in weekly phases. Autosomal dominant mutations of neutrophil elastase (ELA2; 130130), found in lysosome-like granules, cause cyclic hematopoiesis and most cases of the pre-leukemic disorder severe congenital neutropenia (SCN; 202700) in humans. A similar autosomal recessive disease of dogs, canine cyclic hematopoiesis (Lothrop et al., 1987), is not caused by mutations in ELA2. Canine cyclic hematopoiesis is also known an gray collie syndrome because it arose in this breed and affected dogs have hypopigmented coats; the disorder resembles human Hermansky-Pudlak syndrome type 2. Benson et al. (2003) showed that homozygous mutation of the AP3B1 gene, which directs trans-Golgi export of transmembrane cargo proteins to lysosomes, causes canine cyclic hematopoiesis. C-terminal processing of neutrophil elastase exposes an AP3 interaction signal responsible for redirecting neutrophil elastase trafficking from membranes to granules. Disruption of either neutrophil elastase or AP3 perturbs the intracellular trafficking of neutrophil elastase. Most mutations in ELA2 that cause human cyclic hematopoiesis prevent membrane localization of neutrophil elastase, whereas most mutations in ELA2 that cause SCN lead to exclusive membrane localization.
Dell'Angelica et al. (1999) described a 63-bp deletion in 1 allele of the beta-3A-adaptin cDNA sequence in 2 affected members of a family with Hermansky-Pudlak syndrome-2 (HPS2; 608233). The other allele had a leu540-to-arg substitution (L540R; 603401.0002).
Dell'Angelica et al. (1999) described a CTT-to-CGT substitution at codon 540 of 1 allele of the beta-3A-adaptin cDNA sequence, resulting in a leu540-to-arg (L540R) substitution in 2 affected members of a family with Hermansky-Pudlak syndrome-2 (HPS2; 608233). The other allele had a 63-bp deletion (603401.0001).
In a patient with Hermansky-Pudlak syndrome-2 (HPS2; 608233), Clark et al. (2003) identified compound heterozygosity for mutations in the AP3B1 gene. One mutation was a 1-bp insertion (G) at nucleotide 1618 in exon 15, resulting in a frameshift and premature stop codon at position 565. The other mutation was a T-to-C transition at position +6 of the splice site in intron 14 (603401.0004), leading to a 39-bp insertion and the introduction of a stop codon at amino acid 496.
For discussion of the splice site mutation in the AP3B1 gene that was found in compound heterozygous state in a patient with Hermansky-Pudlak syndrome-2 (HPS2; 608233) by Clark et al. (2003), see 603401.0003.
Kotzot et al. (1994) described an inbred Turkish family in which a boy and a girl related as first cousins, and in each case the offspring of consanguineous parents, had tyrosinase-positive oculocutaneous albinism, recurrent bacterial infections, granulocytopenia, intermittent thrombocytopenia, microcephaly, protruding midface, rough and projecting hair, and mild mental retardation (HPS2; 608233). Using genetic linkage analysis and targeted gene sequencing, Jung et al. (2006) defined a homozygous genomic deletion in AP3B1. The mutation led to in-frame skipping of exon 15 and thus perturbed proper assembly of the heterotetrameric AP3 complex. Despite distinct ultramorphologic changes suggestive of aberrant vesicular maturation, no functional aberrations were detected in neutrophil granulocytes. However, a comprehensive immunologic assessment revealed that natural killer (NK) and NKT-cell numbers were reduced in the AP3-deficient patients. The findings extended the clinical and molecular phenotype of human AP3 deficiency and provided insight into the role of the AP3 complex for the innate immune system. The deleted interval spanned 8,168 bp, including a large part of intron 14, the complete exon 15, and a small part of intron 15. Loss of exon 15 resulted in the absence of amino acid 49 to 550 while preserving the reading frame.
In a patient with Hermansky-Pudlak syndrome-2 (HPS2; 608233), Enders et al. (2006) identified a homozygous c.1029A-T transversion (c.1029A-T, NM_003664) in exon 8 of the AP3B1 gene, resulting in an arg302-to-ter (R302X) substitution. Both parents were heterozygous for the mutation. The patient later developed lethal hemophagocytic lymphohistiocytosis (HLH, see 267700).
In a child of Native American origin with Hermansky-Pudlak syndrome-2 (HPS2; 608233), Huizing et al. (2002) identified compound heterozygosity for 2 mutations in the AP3B1 gene: a c.1578C-T transition in exon 15 resulting in an arg509-to-ter (R509X) substitution, and a c.2028G-T transversion in exon 18 resulting in a glu659-to-ter (E659X; 603401.0008) substitution. Northern blot analysis detected no AP3B1 mRNA transcripts in the patient's cells, suggestive of nonsense-mediated mRNA decay. The child had a severe phenotype with neutropenia, recurrent bacterial infections, dysmorphic facies, oculocutaneous albinism, and developmental delay.
For discussion of the glu659-to-ter (E659X) mutation in the AP3B1 gene that was found in compound heterozygous state in a patient with Hermansky-Pudlak syndrome-2 (HPS2; 608233) by Huizing et al. (2002), see 603401.0007.
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Zhen, L., Jiang, S., Feng, L., Bright, N. A., Peden, A. A., Seymour, A. B., Novak, E. K., Elliott, R., Gorin, M. B., Robinson, M. S., Swank, R. T. Abnormal expression and subcellular distribution of subunit proteins of the AP-3 adaptor complex lead to platelet storage pool deficiency in the pearl mouse. Blood 94: 146-155, 1999. [PubMed: 10381507]