Alternative titles; symbols
HGNC Approved Gene Symbol: RAB3GAP1
Cytogenetic location: 2q21.3 Genomic coordinates (GRCh38) : 2:135,052,292-135,176,396 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q21.3 | Martsolf syndrome 2 | 619420 | Autosomal recessive | 3 |
| Warburg micro syndrome 1 | 600118 | Autosomal recessive | 3 |
Members of the RAB3 protein family (see RAB3A; 179490) are implicated in regulated exocytosis of neurotransmitters and hormones. RAB3GAP, which is involved in regulation of RAB3 activity, is a heterodimeric complex consisting a 130-kD catalytic subunit and a 150-kD noncatalytic subunit (609275). RAB3GAP specifically converts active RAB3-GTP to the inactive form RAB3-GDP (Aligianis et al., 2005).
Fukui et al. (1997) isolated a protein from rat brain that showed GAP activity for Rab3a. They used peptide sequences from this Rab3gap to clone a corresponding cDNA from a human brain library. The human RAB3GAP cDNA encodes a 981-amino acid polypeptide. Northern blot analysis showed that RAB3GAP was ubiquitously expressed in human tissues as a 4.5-kb mRNA.
By coimmunoprecipitation of rat brain synaptic soluble fractions, Nagano et al. (1998) found a strong direct interaction between a 150-kD protein (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.
Aligianis et al. (2005) determined that the RAB3GAP1 gene contains 24 exons.
Handley et al. (2013) identified an alternative transcript of RAB3GAP1, ENST00000539493, with an alternative first coding exon. After cloning from human cDNA, sequencing confirmed that the cloned transcript contained the alternative first coding exon, but the 3-prime portion of the coding sequence was identical to that of the full-length transcript. The alternative transcript thus encodes a protein that lacks the first 50 N-terminal amino acids of its full-length counterpart, but includes the entire C-terminal RABGAP domain.
By genomic sequence analysis, Aligianis et al. (2005) mapped the RAB3GAP1 gene to chromosome 2q21.3.
Warburg Micro Syndrome 1
Warburg Micro syndrome-1 (WARBM1; 600118) is characterized by ocular and neurodevelopmental defects and hypothalamic hypogenitalism. Aligianis et al. (2005) identified inactivating mutations in the RAB3GAP1 gene (e.g., 602536.0001) in 5 consanguineous kindreds with Warburg Micro syndrome linked to chromosome 2q21.3, but not in 3 unlinked kindreds. Investigation of an additional 10 families identified germline inactivating mutations in 7 families. The findings indicated that RAB3GAP1 is essential for normal eye and brain development. Aligianis et al. (2005) suggested that microgenitalia may result from hypothalamic hypogonadotropism, and the ocular developmental defects and neurodevelopmental abnormalities may be linked to abnormal neurotransmitter vesicular transport and exocytosis.
In 7 patients with Warburg Micro syndrome-1 from 5 families with Turkish, Palestinian, Danish, and Guatemalan backgrounds, Morris-Rosendahl et al. (2010) identified homozygosity for 5 different truncating RAB3GAP1 mutations, respectively (see, e.g., 602536.0006 and 602536.0007).
Handley et al. (2013) screened the RAB3GAP1, RAB3GAP2 (609275), and RAB18 (602207) genes in patients diagnosed with WARBM or Martsolf syndrome (see 212720) and identified homozygosity or compound heterozygosity for mutations in RAB3GAP1 in patients with WARBM from 42 families (see, e.g., 602536.0003; 602536.0008-602536.0011; 602536.0015). Handley et al. (2013) noted that 2 of the variants were missense mutations: homozygosity for T18P (602536.0010) was identified in affected children from 5 unrelated families of various ethnic origins, and homozygosity for E24V (602536.0011) in an Egyptian family. Both missense mutations occurred at highly conserved residues and segregated with disease in each of the families; these mutations were not found in 270 control chromosomes, and the affected children all had typical eye, brain, and genital findings that were consistent with a diagnosis of WARBM.
Abdel-Hamid et al. (2020) sequenced the RAB3GAP1 and RAB3GAP2 genes in 34 patients from Egypt diagnosed with WARBM (27 patients) or Martsolf syndrome (7 patients) and identified homozygosity or compound heterozygosity for mutations in RAB3GAP1 in 22 patients with WARBM1 from 17 families. Nine of the mutations were novel, all of which were absent from the dbSNP, 1000 Genomes Project, and gnomAD databases. All but one of the mutations were frameshift, nonsense, or splice site mutations; the exception was a homozygous deletion of all exons of the gene (602536.0012) in patient 18.
In 2 sibs, born to consanguineous parents (family 2), with WARBM1, Koparir et al. (2019) identified homozygosity for an insertion/deletion mutation (602536.0015) in the RAB3GAP1 gene. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family.
Martsolf Syndrome 2
In 2 sibs with Martsolf syndrome-2 (MARTS2; 619420), born to consanguineous Egyptian parents (family K7), Handley et al. (2013) identified a homozygous frameshift mutation in the RAB3GAP1 gene (602536.0013). Studies in cDNA from one of the sibs showed increased expression of a region that contains an overlap between the full-length RAB3GAP1 transcript and an alternative RAB3GAP1 transcript. Handley et al. (2013) hypothesized that increased expression of the alternative transcript may have a compensatory effect on the loss of full-length protein, thus leading to Martsolf syndrome rather than the more severe Warburg Micro syndrome.
In a patient with Martsolf syndrome-2, who was born to consanguineous Turkish parents (family 1), Koparir et al. (2019) identified a homozygous splice site mutation in the RAB3GAP1 gene (602536.0014). The mutation was shown to result in reduced RAB3GAP1 expression.
Sakane et al. (2006) found that p130-deficient mice were viable and fertile. Unlike Micro syndrome patients, they showed no ocular and neurodevelopmental defects, and the layered structure of the cerebral cortex and the hippocampus was no different from wildtype brains. In the hippocampal CA1 and CA3 regions, Rab3a colocalized with synapsin I (SYN1; 313440) at presynaptic terminals in both p130-deficient mice and wildtype mice. Expression of p150 was severely attenuated in p150-deficient mice, presumably due to its destabilization in the absence of p130. Functionally, loss of p130 resulted in inhibition of Ca(2+)-dependent glutamate release from cerebrocortical synaptosomes and altered short-term plasticity in the hippocampal CA1 region. Sakane et al. (2006) concluded that RAB3GAP regulates synaptic transmission and plasticity by limiting the amount of GTP-bound RAB3A.
In affected members of 2 Pakistani kindreds segregating Warburg Micro syndrome-1 (WARBM1; 600118), Aligianis et al. (2005) identified a homozygous 1-bp deletion of C at nucleotide 2801 in the last exon of the RAB3GAP1 gene. The mutation resulted in a frameshift that added 38 amino acids to the C terminus of the protein.
Aligianis et al. (2005) identified a homozygous acceptor splice site mutation in intron 7 of the RAB3GAP1 gene, an A-to-G transition at position -2, in affected individuals of 3 apparently unrelated kindreds segregating Warburg Micro syndrome-1 (WARBM1; 600118), including the family in which Warburg Micro syndrome was first described (Warburg et al., 1993). All 3 of these families (K5, K9, and K10) were of Pakistani origin, and genotyping at 5 closely linked microsatellite markers was consistent with a common haplotype, suggestive of a founder effect.
In affected members of a Turkish family segregating Warburg Micro syndrome-1 (WARBM1; 600118), Aligianis et al. (2005) identified a homozygous donor splice site mutation in intron 8 of the RAB3GAP1 gene, a G-to-A transition at position +1. The mutation resulted in skipping of exon 8 and, consequently, a frameshift.
Yuksel et al. (2007) identified homozygosity for the same mutation (748+1G-A) in a 4-year-old Turkish boy with Warburg Micro syndrome.
In affected individuals from 5 unrelated Turkish families segregating WARBM, Handley et al. (2013) identified homozygosity for the c.748+1G-A splice site mutation in the RAB3GAP1 gene. Haplotype analysis confirmed that this is a founder mutation.
In affected members of a consanguineous Lebanese family with a phenotype resembling that of Warburg Micro syndrome-1 (WARBM1; 600118), previously reported by Megarbane et al. (1999), Aligianis et al. (2005) identified homozygosity for a 2011C-T transition in exon 18 of the RAB3GAP1 gene, resulting in an arg671-to-ter (R671X) substitution.
In a 2-year-old Egyptian boy with features consistent with Micro syndrome, Abdel-Salam et al. (2007) identified homozygosity for the R671X mutation in the RAB3GAP1 gene.
In affected members of a consanguineous Mexican family segregating Warburg Micro syndrome-1 (WARBM1; 600118), previously reported by Graham et al. (2004), Aligianis et al. (2005) identified homozygosity for a 1734G-A transition in exon 17 of the RAB3GAP1 gene, resulting in a trp578-to-ter (W578X) substitution.
In a female infant with Warburg Micro syndrome-1 (WARBM1; 600118), born of nonconsanguineous Danish parents, Morris-Rosendahl et al. (2010) identified homozygosity for a 1410C-A transversion in exon 15 of the RAB3GAP1 gene, predicted to result in a tyr470-to-ter (Y470X) substitution. The unaffected parents were heterozygous for the mutation. Analysis of 9 polymorphic markers flanking the RAB3GAP1 gene revealed a homozygous haplotype in the patient that was shared by her unrelated heterozygous parents, suggesting a possible founder effect for the mutation in the Danish population.
In a brother and sister with Warburg Micro syndrome-1 (WARBM1; 600118), born of distantly related Guatemalan parents, Morris-Rosendahl et al. (2010) identified homozygosity for a 7-bp deletion/6-bp insertion (264delAAAGGATinsTTATTA) in exon 4 of the RAB3GAP1 gene, resulting in a frameshift and premature stop at codon 90. The unaffected parents were heterozygous for the mutation.
In a Czech boy with microcephaly, microphthalmia, cataract, mental retardation, progressive spastic diplegia, and hypogenitalism (WARBM1; 600118), who was originally described by Seemanova and Lesny (1996), Handley et al. (2013) identified compound heterozygosity for a splice site transition in intron 10 (c.899+1G-A) of the RAB3GAP1 gene, and a 19-bp insertion in exon 18 (c.2055_2056insGCTCTCAGATATGGAGTCT; 602536.0009), causing a frameshift predicted to result in a premature termination codon (Phe686AlafsTer20). The proband's mother, a maternal aunt, and maternal grandmother were heterozygous for the splicing mutation, whereas his father was heterozygous for the frameshift mutation.
For discussion of the 19-bp insertion in the RAB3GAP1 gene (c.2055_2056insGCTCTCAGATATGGAGTCT) that was found in compound heterozygous state in a patient with Warburg Micro syndrome-1 (WARBM1; 600118) by Handley et al. (2013), see 602536.0008.
In children from 5 unrelated families of various ethnic origins, including Turkish, Pakistani, and Moroccan, who had Warburg Micro syndrome-1 (WARBM1; 600118), Handley et al. (2013) identified homozygosity for a c.52A-C transversion in exon 2 of the RAB3GAP1 gene, resulting in a thr18-to-pro (T18P) substitution at a highly conserved residue. The mutation segregated with disease in each of the families and was not found in 270 control chromosomes. The affected children all had typical eye, brain, and genital findings consistent with a diagnosis of WARBM.
In 2 affected children from an Egyptian family segregating Warburg Micro syndrome-1 (WARBM1; 600118), Handley et al. (2013) identified homozygosity for a c.71A-T transversion in exon 2 of the RAB3GAP1 gene, resulting in a glu24-to-val (E24V) substitution at a highly conserved residue. The mutation segregated with disease in the family and was not found in 270 control chromosomes. Both children had typical eye, brain, and genital findings consistent with a diagnosis of WARBM.
In an 11-year-old boy (patient 18, family 14), born to consanguineous Egyptian parents, with Warburg Micro syndrome-1 (WARBM1; 600118), Abdel-Hamid et al. (2020) identified homozygosity for a whole-gene deletion in the RAB3GAP1 gene. The mutation was identified after repeated failure of RAB3GAP1 to amplify on PCR, and was confirmed by copy number analysis using qPCR. The patient's parents had 50% reduction of RAB3GAP1 on qPCR.
In 2 sibs, born to consanguineous Egyptian parents (family K7), with Martsolf syndrome-2 (MARTS2; 619420), Handley et al. (2013) identified a homozygous 1-bp deletion (c.9delC, NM_012233.2) in exon 1 of the RAB3GAP1 gene, predicted to result in a frameshift and premature termination (Asp4ThrfsTer51). The mutation segregated with the disorder in the family.
In a 14-year-old girl with Martsolf syndrome-2 (MARTS2; 619420), who was born to consanguineous Turkish parents (family 1), Koparir et al. (2019) identified a homozygous G-to-C transversion at the -1 position of intron 22 (c.2607-1G-C, NM_001172435) of the RAB3GAP1 gene, which resulted in the skipping of exon 23. The mutation, which was identified by homozygosity mapping and whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents. The mutation was not present in the 1000 Genomes Project or Exome Variant Server databases or in an in-house exome database. Studies in cDNA from patient blood cells showed that the mutation resulted in reduced RAB3GAP1 expression compared to a control sample.
In 2 sibs, born to consanguineous parents (family 2), with Warburg Micro syndrome-1 (WARBM1; 600118), Koparir et al. (2019) identified homozygosity for an insertion/deletion mutation (c.2187_2188delinsCT, NM_001172435.1) in exon 19 of the RAB3GAP1 gene, resulting in a frameshift and premature termination (Met729_Lys730delinsIleTer). The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents. The mutation was not present in the 1000 Genomes Project or Exome Variant Server databases or in an in-house exome database. Functional studies were not performed.
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