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APC2 REGULATOR OF WNT SIGNALING PATHWAY 2; APC2

APC2 REGULATOR OF WNT SIGNALING PATHWAY 2; APC2

Alternative titles; symbolsAPC2 GENEAPC-LIKE; APCLHGNC Approved Gene Symbol: APC2Cytogenetic location: 19p13.3 Genomic coordinates (GRCh38): 19:1,446,267-1,4...

Alternative titles; symbols

  • APC2 GENE
  • APC-LIKE; APCL

HGNC Approved Gene Symbol: APC2

Cytogenetic location: 19p13.3 Genomic coordinates (GRCh38): 19:1,446,267-1,473,243 (from NCBI)

▼ Description
The APC2 gene, which is preferentially expressed in postmitotic neurons, is involved in brain development through its regulation of neuronal migration and axon guidance. It interacts with actin fibers and stabilizes microtubules (summary by Almuriekhi et al., 2015).

▼ Cloning and Expression
By searching an EST database for sequences related to APC (611731), followed by screening a brain cDNA library, Nakagawa et al. (1998) cloned APC2, which they called APCL. The deduced 2,303-amino acid protein contains an N-terminal coiled-coil domain, followed by an armadillo domain and five 20-amino acid repeats. APC and APC2 are highly similar in their N-terminal halves, but share no similarity in their C-terminal halves. Northern blot analysis detected an APC2 transcript of more than 10 kb expressed specifically and abundantly in brain.

Van Es et al. (1999) cloned mouse and human APC2. The mouse protein contains 2,274 amino acids. RNA dot blot analysis of human tissues showed APC2 expression throughout the central nervous system.

▼ Gene Structure
Nakagawa et al. (1998) determined that the APC2 gene contains 14 exons and spans 40 kb.

Lee et al. (2019) stated that the APC2 gene contains 15 exons, the first of which is noncoding.

▼ Mapping
By FISH, Nakagawa et al. (1998) and van Es et al. (1999) mapped the APC2 gene to chromosome 19p13.3. Van Es et al. (1999) mapped the mouse Apc2 gene to a region of chromosome 10 that shares homology of synteny with human chromosome 19p13.3.

▼ Gene Function
Nakagawa et al. (1998) found that the 20-amino acid repeat domain of APCL could bind beta-catenin (CTNNB1; 116806) and deplete the intracellular beta-catenin pool. A reporter gene assay revealed that APCL could regulate interaction of beta-catenin with T cell-specific transcription factors (see TCF7; 189908), although less efficiently than APC.

Using mutation analysis, van Es et al. (1999) showed that the 2 SAMP domains of mouse Apc2 were required to bind conductin (AXIN2; 604025).

▼ Molecular Genetics
Intellectual Developmental Disorder, Autosomal Recessive 74

In 2 sibs, born of consanguineous Egyptian parents, with autosomal recessive intellectual developmental disorder-74 (MRT74; 617169), Almuriekhi et al. (2015) identified a homozygous truncating mutation in the APC2 gene (612034.0001). The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family. Expression of the mutation in neuronal cells showed that the mutant protein had abnormal punctate localization, was not distributed along microtubules, did not colocalize with F-actin, and had lost microtubule stabilization activity, all consistent with a loss of function. Studies in murine cells indicated that expression of NSD1 (606681) controlled neuronal migration through the induction of APC2. Almuriekhi et al. (2015) suggested that subtle neuronal migration defects in the patients, although not apparent on imaging, may underlie the impaired intellectual development in this disorder.

In a 27-year-old Italian woman with intellectual impairment, macrocephaly, and seizures with eyelid myoclonus, Mastrangelo et al. (2020) identified compound heterozygosity for missense mutations in the APC2 gene (P2207L, 612034.0006; V355I, 612034.0007) that segregated with disease in the family.

Complex Cortical Dysplasia with Other Brain Malformations 10

In 12 patients from 8 unrelated families with complex cortical dysplasia with other brain malformations-10 (CDCBM10; 618677), Lee et al. (2019) identified homozygous or compound heterozygous mutations in the APC2 gene (see, e.g., 612034.0002-612034.0005). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. None of the variants were found in the 1000 Genomes Project or gnomAD databases. Functional studies of the variants and studies of patient cells were not performed, but all of the variants were predicted to result in a loss of function. The patients were ascertained through collaborative efforts focusing on patients with confirmed lissencephaly. Seven of the families were consanguineous and of Middle Eastern origin.

▼ Animal Model
Almuriekhi et al. (2015) found that Apc2-null mice had impaired learning and memory associated with an abnormal head shape, dilated ventricles, and thin corpus callosum. Knockdown of Nsd1 (606681) significantly reduced the expression of Apc2, indicating that Apc2 is a downstream effector of Nsd1. Nsd1 knockdown also caused impaired cerebral neuronal migration and layering defects similar to that observed in Apc2-null mice, and expression of Apc2 in Nsd1-null cells rescued the defect. The findings indicated that expression of NSD1 controlled neuronal migration through the induction of APC2.

By immunostaining of the developing mouse cortex, Shintani et al. (2012) found expression of the Apc2 gene in postmitotic migrating neuronal cells, but not in glial cells. Apc2-null mice showed severe defects in neuronal lamination in the cortex, hippocampus, cerebellum, and olfactory bulb, consistent with impaired directional neuronal migration. In vitro functional studies in isolated cerebellar granule cells showed abnormal actin reorganization after stimulation with BDNF (113505), which was associated with attenuated signaling through Rac1 (602048), TrkB (600456), and Cdc42 (116952). The findings suggested that Apc2 is a mediator of the cytoskeletal regulation at the leading edge of migrating neurons in response to extracellular guiding molecules during brain development.

▼ ALLELIC VARIANTS ( 7 Selected Examples):

.0001 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL RECESSIVE 74
APC2, 1-BP DUP, 5199C
In 2 sibs, born of consanguineous Egyptian parents, with autosomal recessive intellectual developmental disorder-74 (MRT74; 617169), Almuriekhi et al. (2015) identified a homozygous 1-bp duplication (c.5199dupC, NM_005883) in the APC2 gene, resulting in a frameshift and premature termination (Lys1734GlnfsTer418). The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family. Expression of the mutation in neuronal cells showed that the mutant protein had abnormal punctate localization, was not distributed along microtubules, did not colocalize with F-actin, and had lost microtubule stabilization activity, all consistent with a loss of function. In cultured murine cortical neurons, wildtype Apc2 was distributed along microtubules throughout the neurites, growth cones, and cell bodies, whereas mutant Apc2 was concentrated in cell bodies, suggesting that the mutation results in abnormal distribution.

.0002 CORTICAL DYSPLASIA, COMPLEX, WITH OTHER BRAIN MALFORMATIONS 10
APC2, GLN361TER
In 2 sibs, born of consanguineous Egyptian parents (family 1), with complex cortical dysplasia with other brain malformations-10 (CDCBM10; 618677), Lee et al. (2019) identified a homozygous c.1081C-T transition (c.1081C-T, NM_005883.2) in exon 9 of the APC2 gene, resulting in a gln361-to-ter (Q361X) substitution in the armadillo repeat domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The mutation was not found in the 1000 Genomes Project or gnomAD databases. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in a loss of function.

.0003 CORTICAL DYSPLASIA, COMPLEX, WITH OTHER BRAIN MALFORMATIONS 10
APC2, 1-BP DEL, 6645C
In 2 sibs, born of consanguineous Egyptian parents (family 3), with complex cortical dysplasia with other brain malformations-10 (CDCBM10; 618677), Lee et al. (2019) identified a homozygous 1-bp deletion (c.6645delC, NM_005883.2) in exon 15 of the APC2 gene, predicted to result in a frameshift and premature termination (Ala2217ProfsTer118). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The mutation was not found in the 1000 Genomes Project or gnomAD databases. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in a loss of function.

.0004 CORTICAL DYSPLASIA, COMPLEX, WITH OTHER BRAIN MALFORMATIONS 10
APC2, SER246TER
In 2 sibs, born of consanguineous Turkish parents (family 6), with complex cortical dysplasia with other brain malformations-10 (CDCBM10; 618677), Lee et al. (2019) identified a homozygous c.737C-A transversion (c.737C-A, NM_005883.2) in exon 8 of the APC2 gene, resulting in a ser246-to-ter (S246X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The mutation was not found in the 1000 Genomes Project or gnomAD databases. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in a loss of function.

.0005 CORTICAL DYSPLASIA, COMPLEX, WITH OTHER BRAIN MALFORMATIONS 10
ACP2, 7-BP DEL, NT2840
In 2 sibs, born of consanguineous Syrian parents (family 7), with complex cortical dysplasia with other brain malformations-10 (CDCBM10; 618677), Lee et al. (2019) identified a homozygous 7-bp deletion (c.2840_2846del, NM_005883.2) in exon 15 of the APC2 gene, resulting in a frameshift and premature termination (Leu947HisfsTer88). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The mutation was not found in the 1000 Genomes Project or gnomAD databases. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in a loss of function.

.0006 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL RECESSIVE 74
APC2, PRO2207LEU

In a 27-year-old Italian woman with intellectual impairment, macrocephaly, and seizures with eyelid myoclonus (MRT74; 617169), Mastrangelo et al. (2020) identified compound heterozygosity for missense mutations in the APC2 gene: a c.6620C-T transition (c.6620C-T, NM_005883), resulting in a pro2207-to-leu (P2207L) substitution at a well-conserved residue, and a c.1063G-A transition, resulting in a val355-to-ile (V355I) substitution. Her unaffected father was heterozygous for the P2207L variant, which was not found in the gnomAD database, whereas her unaffected mother and brother were heterozygous for the V355I variant, which was present in gnomAD at a minor allele frequency of 5.04 x 10(-5), only in heterozygosity.

.0007 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL RECESSIVE 74
APC2, VAL355ILE

For discussion of the c.1063G-A transition (c.1063G-A, NM_005883) in the APC2 gene, resulting in a val355-to-ile (V355I) substitution, that was found in compound heterozygous state in a 27-year-old Italian woman with intellectual impairment, macrocephaly, and seizures with eyelid myoclonus (MRT74; 617169) by Mastrangelo et al. (2020), see 612034.0006.

Tags: 19p13.3