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ADAPTOR-RELATED PROTEIN COMPLEX 3, BETA-2 SUBUNIT; AP3B2

ADAPTOR-RELATED PROTEIN COMPLEX 3, BETA-2 SUBUNIT; AP3B2

Alternative titles; symbolsADAPTOR-RELATED PROTEIN COMPLEX 3B, NEURON-SPECIFIC, BETA-3BAP3B, BETA-3BNEURONAL ADAPTIN-LIKE PROTEIN, BETA SUBUNIT; NAPTBHGNC Approv...

Alternative titles; symbols

  • ADAPTOR-RELATED PROTEIN COMPLEX 3B, NEURON-SPECIFIC, BETA-3B
  • AP3B, BETA-3B
  • NEURONAL ADAPTIN-LIKE PROTEIN, BETA SUBUNIT; NAPTB

HGNC Approved Gene Symbol: AP3B2

Cytogenetic location: 15q25.2 Genomic coordinates (GRCh38): 15:82,659,280-82,709,874 (from NCBI)

▼ Description

Adaptor protein-3 (AP3) is a heterotetrameric vesicle-coat protein complex. Some AP3 subunits are ubiquitously expressed, whereas others are expressed exclusively in neurons. The neuron-specific AP3 complex, which includes AP3B2, is thought to serve neuron-specific functions such as neurotransmitter release (Grabner et al., 2006).

▼ Gene Function

The beta subunit of neuronal adaptin-like protein (beta-NAP) is the target antigen in human paraneoplastic neurologic disorders (Newman et al., 1995; Simpson et al., 1996). By use of the yeast 2-hybrid system, Lim et al. (1998) demonstrated that ATM protein (607585), which is mutated in ataxia-telangiectasia, binds to beta-adaptin (600157), one of the components of the complex that is involved in clathrin-mediated endocytosis of receptors. The ATM protein was also found to interact in vitro with beta-NAP. Lim et al. (1998) commented on the possible significance of cerebellar degeneration as a conspicuous feature of ataxia-telangiectasia and as an autoantigen in a patient with paraneoplastic cerebellar degeneration.

Grabner et al. (2006) showed that overexpression of neuronal AP3 subunits, including Ap3b2, in mouse chromaffin cells produced a large number of small-volume vesicles that released relatively small amounts of neurotransmitter. In contrast, depleting AP3 produced large-diameter vesicles that released large amounts of neurotransmitter. The authors concluded that interaction of neuronal AP3 with vesicles regulates vesicle neurotransmitter content.

▼ Mapping

Gross (2017) mapped the AP3B2 gene to chromosome 15q25.2 based on an alignment of the AP3B2 sequence (GenBank AF022152) with the genomic sequence (GRCh38).

The mouse neuronal vesicle coat protein gene Naptb maps to chromosome 7, in a region syntenic with human chromosome region 15q (Fletcher et al., 1997).

▼ Molecular Genetics

In 12 patients from 8 unrelated families with developmental and epileptic encephalopathy-48 (DEE48; 617276), Assoum et al. (2016) identified homozygous or compound heterozygous splice site, nonsense, or frameshift mutations in the AP3B2 gene (see, e.g., 602166.0001-602166.0005). The families were of various ethnic origins and 6 were consanguineous. Mutations in the first 2 families were found by whole-exome sequencing of 57 individuals; mutations in subsequent families were found by direct sequencing of this candidate gene in 86 individuals or through the Matchmaker Exchange Initiative. Analysis of patient cells from 2 families suggested a loss-of-function effect of the mutations; additional functional studies were not performed.

In 2 unrelated patients, each born of consanguineous parents, with DEE48, Anazi et al. (2017) identified a homozygous truncating mutation in the AP3B2 gene (602166.0006). The mutation, which was found by exome sequencing of 337 individuals with intellectual disability, segregated with the disorder in the families. Functional studies of the variant and studies of patient cells were not performed. Haplotype analysis suggested a common origin.

▼ ALLELIC VARIANTS ( 6 Selected Examples):

.0001 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 48
AP3B2, 1182G-A

In a 25-year-old woman (patient 1) with developmental and epileptic encephalopathy-48 (DEE48; 617276), Assoum et al. (2016) identified compound heterozygous splice site mutations in the AP3B2 gene: a c.1182G-A transition (c.1182G-A, NM_004644.4) in the last base of exon 10, resulting in the in-frame skipping of exon 10, and a G-to-C transversion in intron 9 (c.1110+1G-C; 602166.0002), resulting in the skipping of exon 9 or exons 9 and 10 and frameshifts in the coding sequence. These mutant transcripts were subject to nonsense-mediated mRNA decay. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Neither mutation was found in the ExAC database. The patient had global developmental delay apparent in early infancy and developed tonic-clonic seizures at 6 months of age.

.0002 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 48
AP3B2, IVS9DS, G-C, +1

For discussion of the G-to-C transversion in intron 9 of the AP3B2 gene (c.1110+1G-C, NM_004644.4), resulting in the skipping of exon 9 or exons 9 and 10 and frameshifts in the coding sequence, that was found in compound heterozygous state in a patient with developmental and epileptic encephalopathy-48 (DEE48; 617276) by Assoum et al. (2016), see 602166.0001.

.0003 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 48
AP3B2, EX14DEL

In a girl (patient 2), born of consanguineous Algerian parents, with developmental and epileptic encephalopathy-48 (DEE48; 617276), Assoum et al. (2016) identified a homozygous deletion of exon 14 (c.1489-245_1665+2029del, NM_004644.4) of the AP3B2 gene. The deletion, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in the ExAC database. Patient cells showed a large decrease in mutant AP3B2 mRNA, suggesting nonsense-mediated mRNA decay. The patient had onset of infantile spasms at 4 months of age.

.0004 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 48
AP3B2, 4-BP DEL, 2522TCAC

In 2 members (patients 3 and 4) of a large consanguineous family of French origin with developmental and epileptic encephalopathy-48 (DEE48; 617276), Assoum et al. (2016) identified a homozygous 4-bp deletion (c.2522_2525delTCAC, NM_004644.4) in exon 21 of the AP3B2 gene, resulting in a frameshift and premature termination (Leu841GlnfsTer10). The mutation was found by Sanger sequencing of the AP3B2 gene in 86 unrelated individuals with early-onset epileptic encephalopathy. It segregated with the disorder in the family and was not found in the ExAC database. Functional studies of the variant and studies of patient cells were not performed. The patients had onset of seizures in the first months of life.

.0005 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 48
AP3B2, ARG67TER

In 2 sisters (patients 7 and 8), born of consanguineous Pakistani parents, with developmental and epileptic encephalopathy-48 (DEE48; 617276), Assoum et al. (2016) identified a homozygous c.199C-T transition (c.199C-T, NM_004644.4) in the AP3B2 gene, resulting in an arg67-to-ter (R67X) substitution. The mutation segregated with the disorder in the family and was not found in the ExAC database. Functional studies and studies of patient cells were not performed. One patient had neonatal onset of seizures, whereas the other did not have seizures. Both had significant developmental delay with failure to thrive, microcephaly, poor visual tracking, and inability to sit or eat.

.0006 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 48
AP3B2, 1-BP DEL, NT1837

In 2 unrelated patients (16DG0295 and 16DG0606), each born of consanguineous parents, with developmental and epileptic encephalopathy-48 (DEE48; 617276), Anazi et al. (2017) identified a homozygous 1-bp deletion (c.1837del, NM001278512.1) in the AP3B2 gene, resulting in a frameshift and premature termination (Glu613SerfsTer182). The mutation, which was found by exome sequencing, segregated with the disorder in the families. Functional studies of the variant and studies of patient cells were not performed. Haplotype analysis suggested a common origin.

Tags: 15q25.2