Alternative titles; symbols
HGNC Approved Gene Symbol: RAB3GAP2
Cytogenetic location: 1q41 Genomic coordinates (GRCh38) : 1:220,148,293-220,272,453 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q41 | Martsolf syndrome 1 | 212720 | Autosomal recessive | 3 |
| Warburg micro syndrome 2 | 614225 | Autosomal recessive | 3 |
Members of the RAB3 protein family (see RAB3A; 179490) are implicated in Ca(2+)-dependent exocytosis. RAB3GAP, which is involved in regulation of RAB3 activity, is a heterodimeric complex consisting a 130-kD catalytic subunit (RAB3GAP1; 602536) and a 150-kD noncatalytic subunit (RAB3GAP2) (Nagano et al., 1998).
By database analysis to identify human peptide sequences similar to the 150-kD noncatalytic subunit of rat Rab3gap (p150), followed by PCR, library screening, and 5-prime RACE of a brain cDNA library, Nagano et al. (1998) cloned human p150. The deduced protein contains 1,393 amino acids. Northern blot analysis detected a 7.5-kb transcript in all human tissues examined. Western blot analysis of subcellular fractionated rat brain detected p150 enriched in the synaptic soluble fraction.
By sequencing clones obtained from a size-fractionated brain cDNA library, Nagase et al. (1998) cloned KIAA0839. RT-PCR ELISA detected highest expression in brain, followed by kidney, ovary, and heart. Intermediate expression was detected in all other tissues examined.
Aligianis et al. (2006) stated that the RAB3GAP2 gene comprises 36 exons.
Gross (2017) mapped the RAB3GAP2 gene to chromosome 1q41 based on an alignment of the RAB3GAP2 sequence (GenBank AF004828) with the genomic sequence (GRCh38).
By coimmunoprecipitation of rat brain synaptic soluble fractions, Nagano et al. (1998) found a strong direct interaction between p150 and a 130-kD protein (p130) that showed GAP activity toward Rab3 family members. p150 did not show GAP activity, and the interaction between p150 and p130 did not alter the activity of p130 or the subcellular distribution of the 2 proteins.
In mRNA expression studies of the orthologs of RAB3GAP1 and RAB3GAP2 in zebrafish embryos, Aligianis et al. (2006) demonstrated that, whereas developmental expression of Rab3gap1 was generalized similar to that reported in mice, Rab3gap2 expression was restricted to the central nervous system. These findings were consistent with RAB3GAP2 having a key role in neurodevelopment.
Martsolf Syndrome 1
Aligianis et al. (2006) identified a homozygous missense mutation in the noncatalytic subunit of RAB3GAP (609275.0001) that resulted in abnormal splicing in affected members of a family with Martsolf syndrome (MARTS1; 212720). The heterodimeric complex RAB3GAP consists of a catalytic subunit and a noncatalytic subunit encoded by RAB3GAP1 (602536) and RAB3GAP2, respectively. Expression studies in zebrafish yielded results consistent with RAB3GAP2 having a key role in neurodevelopment. Aligianis et al. (2006) suggested that this may indicate that Warburg micro syndrome (600118), which had been shown to have mutations in RAB3GAP1, and Martsolf syndrome represent a spectrum of disorders. However, Aligianis et al. (2006) detected no RAB3GAP2 mutations in patients with Warburg Micro syndrome. Together, these findings suggested that dysregulation of RAB3GAP may result in a spectrum of phenotypes that range from Warburg micro syndrome to Martsolf syndrome.
In 2 Gambian sisters and a Mexican Hispanic boy with Martsolf syndrome, Handley et al. (2013) identified homozygosity for a missense mutation in the RAB3GAP2 gene (R426C; 609275.0003).
Abdel-Hamid et al. (2020) sequenced the RAB3GAP1 and RAB3GAP2 genes in 34 patients from Egypt diagnosed with WARBM2 (27 patients) or Martsolf syndrome (7 patients). All 7 patients with Martsolf syndrome were homozygous for truncating mutations in the RAB3GAP2 gene (see, e.g., 609275.0007-609275.0008). All of the mutations were absent from the dbSNP, 1000 Genomes Project, and gnomAD databases.
Warburg Micro Syndrome 2
In a patient with Warburg Micro syndrome-2 (WARBM2; 614225), Borck et al. (2011) identified a homozygous in-frame deletion of 9 bp in exon 6 of the RAB3GAP2 gene (609275.0002).
In affected individuals from 7 families with Warburg Micro syndrome, Handley et al. (2013) identified homozygosity for mutations in the RAB3GAP2 gene (see, e.g., 609275.0004-609275.0006).
Abdel-Hamid et al. (2020) sequenced the RAB3GAP1 and RAB3GAP2 genes in 34 patients from Egypt diagnosed with WARBM2 (27 patients) or Martsolf syndrome (7 patients). Two patients with WARBM2 had mutations in the RAB3GAP2, including a truncating mutation and a missense mutation (A841V). The A841V mutation, which was found in patient 28 (family21) was considered to be a variant of unknown significance according to ACMG guidelines. The truncating mutation was absent from the dbSNP, 1000 Genomes Project, and gnomAD databases, and the missense mutation was present in the gnomAD database at an allele frequency of 0.00005172.
Borck et al. (2011) suggested that functionally severe RAB3GAP2 mutations cause Warburg Micro syndrome-2, whereas hypomorphic RAB3GAP2 mutations can result in the milder Martsolf phenotype. They thus proposed that a phenotypic severity gradient may exist in the RAB3GAP-associated disease continuum (the 'Warburg-Martsolf syndrome'), which is presumably determined by the mutant gene and the nature of the mutation.
In 3 sibs from a consanguineous Pakistani family with Martsolf syndrome (MARTS1; 212720), Aligianis et al. (2006) found a homozygous 3154G-T (gly1051 to cys) substitution in the RAB3GAP2 gene. Both parents were heterozygous for this substitution. In studies of lymphocyte RNA, Aligianis et al. (2006) found that the G1051C mutation resulted in 2 transcripts. The substitution is adjacent to the exon 28 splice donor site and resulted in exon 28 skipping and frameshift.
In a girl from a consanguineous Turkish family with Warburg Micro syndrome-2 (WARBM2; 614225), Borck et al. (2011) identified a homozygous 9-bp in-frame deletion (499_507delTTCTACACT) in the RAB3GAP2 gene. The mutation was predicted to lead to the deletion of the amino acids phenylalanine, tyrosine, and threonine at positions 167-169 of the protein (Phe167_Thr169del). The parents were heterozygous carriers of the mutation, which was absent in 288 Turkish and 170 German control chromosomes. RT-PCR on lymphocyte RNA from the patient confirmed the homozygous 9-bp deletion at the mRNA level and detected no aberrant splicing.
In 2 Gambian sisters and a Mexican Hispanic boy with Martsolf syndrome (MARTS1; 212720), Handley et al. (2013) identified homozygosity for a c.1276C-T transition in exon 14 of the RAB3GAP2 gene, resulting in an arg426-to-cys (R426C) substitution at a very highly conserved residue within a WKGYRDA motif.
In 2 affected individuals from a consanguineous Tunisian family with Warburg Micro syndrome-2 (WARBM2; 614225), Handley et al. (2013) identified homozygosity for a c.1434G-A transition in exon 14 of the RAB3GAP2 gene, resulting in a trp478-to-ter (W478X) substitution. The mutation segregated with disease within the family and was not found in 400 control chromosomes.
In 2 affected individuals from a consanguineous Saudi Arabian family with Warburg Micro syndrome-2 (WARBM2; 614225), Handley et al. (2013) identified homozygosity for a c.3637C-T transition in exon 32 of the RAB3GAP2 gene, resulting in an arg1213-to-ter (R1213X) substitution. The mutation segregated with disease within the family and was not found in 400 control chromosomes.
In a Dutch male patient with Warburg Micro syndrome-2 (WARBM2; 614225), Handley et al. (2013) identified homozygosity for a c.3085G-T transversion in exon 26 of the RAB3GAP2 gene, resulting in a glu1029-to-ter (E1029X) substitution. The mutation segregated with disease in the family and was not found in 400 control chromosomes.
In 2 sibs (patients 26 and 27, family 20), born to consanguineous Egyptian parents, with Martsolf syndrome (MARTS1; 212720), Abdel-Hamid et al. (2020) identified homozygosity for a c.2488C-T transition (c.2488C-T, NM_012414.4) in the RAB3GAP2 gene, resulting in a gln830-to-ter (Q830X) substitution. The mutation was not found in the dbSNP, 1000 Genomes Project, and gnomAD databases.
In 2 sibs (patients 29 and 30, family 22), born to consanguineous Egyptian parents, with Martsolf syndrome (MARTS1; 212720), Abdel-Hamid et al. (2020) identified homozygosity for a c.1955T-A transversion (c.1955T-A, NM_012414.4) in the RAB3GAP2 gene, resulting in a leu652-to-ter (L652X) substitution. The mutation was not found in the dbSNP, 1000 Genomes Project, and gnomAD databases.
Abdel-Hamid, M. S., Abdel-Ghafar, S. F., Ismail, S. R., Desouky, L. M., Issa, M. Y., Effat, L. K., Zaki, M. S. Micro and Martsolf syndromes in 34 new patients: refining the phenotypic spectrum and further molecular insights. Clin. Genet. 98: 445-456, 2020. [PubMed: 32740904] [Full Text: https://doi.org/10.1111/cge.13825]
Aligianis, I. A., Morgan, N. V., Mione, M., Johnson, C. A., Rosser, E., Hennekam, R. C., Adams, G., Trembath, R. C., Pilz, D. T., Stoodley, N., Moore, A. T., Wilson, S., Maher, E. R. Mutation in Rab3 GTPase-activating protein (RAB3GAP) noncatalytic subunit in a kindred with Martsolf syndrome. Am. J. Hum. Genet. 78: 702-707, 2006. [PubMed: 16532399] [Full Text: https://doi.org/10.1086/502681]
Borck, G., Wunram, H., Steiert, A., Volk, A. E., Korber, F., Roters, S., Herkenrath, P., Wollnik, B., Morris-Rosendahl, D. J., Kubisch, C. A homozygous RAB3GAP2 mutation causes Warburg Micro syndrome. Hum. Genet. 129: 45-50, 2011. [PubMed: 20967465] [Full Text: https://doi.org/10.1007/s00439-010-0896-2]
Gross, M. B. Personal Communication. Baltimore, Md. 1/11/2017.
Handley, M. T., Morris-Rosendahl, D. J., Brown, S., Macdonald, F., Hardy, C., Bem, D., Carpanini, S. M., Borck, G., Martorell, L., Izzi, C., Faravelli, F., Accorsi, P., and 23 others. Mutation spectrum in RAB3GAP1, RAB3GAP2, and RAB18 and genotype-phenotype correlations in Warburg Micro syndrome and Martsolf syndrome. Hum. Mutat. 34: 686-696, 2013. [PubMed: 23420520] [Full Text: https://doi.org/10.1002/humu.22296]
Nagano, F., Sasaki, T., Fukui, K., Asakura, T., Imazumi, K., Takai, Y. Molecular cloning and characterization of the noncatalytic subunit of the Rab3 subfamily-specific GTPase-activating protein. J. Biol. Chem. 273: 24781-24785, 1998. [PubMed: 9733780] [Full Text: https://doi.org/10.1074/jbc.273.38.24781]
Nagase, T., Ishikawa, K., Suyama, M., Kikuno, R., Hirosawa, M., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Oharo, O. Prediction of the coding sequences of unidentified human genes. XII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 5: 355-364, 1998. [PubMed: 10048485] [Full Text: https://doi.org/10.1093/dnares/5.6.355]