Alternative titles; symbolsBREFELDIN A-INHIBITED GUANINE NUCLEOTIDE EXCHANGE PROTEIN 2; BIG2HGNC Approved Gene Symbol: ARFGEF2Cytogenetic location: 20q13.13 ...
Alternative titles; symbols
HGNC Approved Gene Symbol: ARFGEF2
Cytogenetic location: 20q13.13 Genomic coordinates (GRCh38): 20:48,921,710-49,036,692 (from NCBI)
Togawa et al. (1999) isolated BIG2 from a human frontal cortex cDNA library. BIG2 encodes a protein of 1,785 amino acids containing a Sec7 domain characteristic of other ADP-ribosylation factor (ARF) guanine nucleotide exchange proteins. BIG2 shares 74% overall amino acid identity with BIG1 and 90% identity within the Sec7 domain. By Northern blot analysis, Togawa et al. (1999) detected a 9.4-kb BIG2 transcript in placenta, lung, heart, brain, kidney, and pancreas.
By Northern blot analysis, Sheen et al. (2004) found that mouse Arfgef2 mRNA levels are highest during embryonic periods of ongoing neuronal proliferation and migration, and by in situ hybridization, they found that the mRNA is widely distributed throughout the embryonic CNS.
▼ Gene Function
Togawa et al. (1999) synthesized a 20-kD recombinant BIG2 that accelerated GTP binding by ARFs and was inhibited by BFA.
Sheen et al. (2004) found that the BIG2 protein is required for vesicle and membrane trafficking from the trans-Golgi network. Inhibition of BIG2 by BFA, or by a dominant-negative ARFGEF2 cDNA, decreased cell proliferation in vitro, suggesting a cell-autonomous regulation of neural expansion. Inhibition of BIG2 also disturbed the intracellular localization of such molecules as E-cadherin (192090) and beta-catenin (116806) by preventing their transport from the Golgi apparatus to the cell surface. The findings showed that vesicle trafficking is an important regulator of proliferation and migration during human cerebral cortical development.
Kuroda et al. (2007) showed that elevated cAMP in HepG2 cells caused PKA (see PRKACA; 601639)-catalyzed phosphorylation and nuclear accumulation of BIG1, but not BIG2. Phosphorylation of BIG1 or BIG2 by PKA was associated with decreased BIG1 or BIG2 GEP activity, which could be restored by dephosphorylation by PP1-gamma (PPP1CC; 176914). Kuroda et al. (2007) concluded that cAMP, PKA, and PP1-gamma regulate vesicular traffic via their effects on the phosphorylation status of BIG1 and BIG2.
Using somatic cell hybrid analysis, Togawa et al. (1999) mapped the BIG2 gene to chromosome 20.
▼ Molecular Genetics
Autosomal recessive periventricular heterotopia with microcephaly (ARPHM; 608097) is a severe malformation of the cerebral cortex, characterized by severe developmental delay and recurrent infections (Sheen et al., 2003). By an initial genomewide screen at 10-cM intervals in 2 Turkish families with ARPHM, Sheen et al. (2004) identified shared homozygosity at a single locus on 20q11.21-q13.2, which they refined by further marker analysis. They sequenced several candidate genes in the minimal linkage region, and in each family they identified a homozygous mutation in the ARFGEF2 gene (605371.0001 and 605371.0002).
In 5 members of a consanguineous Palestinian family with periventricular heterotopia with microcephaly, Banne et al. (2013) identified a homozygous mutation in the ARFGEF2 gene (605371.0003). The mutation was found by homozygosity mapping combined with whole-exome sequencing.
▼ ALLELIC VARIANTS ( 3 Selected Examples):
.0001 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE
This variant, formerly titled PERIVENTRICULAR HETEROTOPIA WITH MICROCEPHALY, AUTOSOMAL RECESSIVE, has been reclassified based on the report of Lek et al. (2016).
In affected members of a consanguineous Turkish family with autosomal recessive periventricular heterotopia with microcephaly (ARPHM; 608097), Sheen et al. (2004) identified a 625G-A transition in exon 6 of the ARFGEF2 gene, which produced a nonconservative amino acid substitution, glu209 to lys (E209K).
Lek et al. (2016) noted that the E209K variant has a high allele frequency (0.0121) in the Latino population in the ExAC database, suggesting that it is not pathogenic.
.0002 PERIVENTRICULAR HETEROTOPIA WITH MICROCEPHALY, AUTOSOMAL RECESSIVE
ARFGEF2, PRO81GLN, VAL83LEU, 249delA
In affected members of a consanguineous Turkish family with autosomal recessive periventricular heterotopia with microcephaly (608097), Sheen et al. (2004) identified a complex homozygous mutation in exon 3 of the ARFGEF2 gene, consisting of the nucleotide substitutions 242C-A and 247G-T and the deletion 249delA. These nucleotide changes caused amino acid substitutions pro81 to gln (P81Q) and val83 to leu (V83L) and a translational frameshift at amino acid residue 84, resulting in premature termination of translation after 30 additional abnormal amino acids.
.0003 PERIVENTRICULAR HETEROTOPIA WITH MICROCEPHALY, AUTOSOMAL RECESSIVE
ARFGEF2, IVS14DS, G-A, +1
In 5 members of a consanguineous Palestinian family with periventricular heterotopia with microcephaly (608097), Banne et al. (2013) identified a homozygous G-to-A transition in intron 14 of the ARFGEF2 gene (c.1958+1G-A), resulting in the elimination of 44 nucleotides of the patients' cDNA. The mutation was found by homozygosity mapping combined with whole-exome sequencing and segregated with the disorder in the family. It was not present in the dbSNP (build 132) database or among in-house database variants. The patients had severely delayed psychomotor development, microcephaly, and infantile seizures associated with hypsarrhythmia on EEG, consistent with a clinical diagnosis of West syndrome. Brain MRI showed periventricular heterotopia and thin corpus callosum. No other organ systems were affected.