Alternative titles; symbols
HGNC Approved Gene Symbol: RAC3
Cytogenetic location: 17q25.3 Genomic coordinates (GRCh38): 17:82,031,678-82,034,204 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q25.3 | Neurodevelopmental disorder with structural brain anomalies and dysmorphic facies | 618577 | Autosomal dominant | 3 |
The small G proteins RAC1 (602048), RAC2 (602049), and RAC3 are highly related GTPases belonging to the RHO subfamily of RAS proteins (see 190020) (summary by Haataja et al., 1997).
Haataja et al. (1997) isolated the RAC family member RAC3. RAC3 shares 92% and 89% amino acid identity, respectively, with RAC1 and RAC2 but differs from RAC1 and RAC2 at its C-terminal end, a domain associated with subcellular localization and binding to specific cellular regulators. RAC3 mRNA expression patterns differed from those of RAC2, which is hematopoietic cell-specific, and also from those of RAC1.
Morris et al. (2000) determined the genomic structure of the RAC3 gene. The gene contains 6 exons.
Haataja et al. (1997) mapped the RAC3 gene to 17q23-q25 by study of somatic cell hybrids and of a regional mapping panel for chromosome 17. Courjal et al. (1997) localized the RAC3 gene to 17q24-qter by fluorescence in situ hybridization. By metaphase and interphase FISH analyses, Morris et al. (2000) mapped the RAC3 gene to 17q25.3.
In a girl with neurodevelopmental disorder with structural brain anomalies and dysmorphic facies (NEDBAF; 618577), White et al. (2018) identified a de novo heterozygous missense mutation in the RAC3 gene (A59G; 602050.0001). The mutation was found by exome sequencing and confirmed by Sanger sequencing; functional studies of the variant and studies of patient cells were not performed.
In 5 patients, including 2 half sibs, with NEDBAF, Costain et al. (2019) identified heterozygous missense mutations in the RAC3 gene (602050.0002-602050.0004). The mutations occurred de novo in 3 patients and were suspected to result from maternal gonadal mosaicism in the affected half sibs. The mutations, which were found by exome sequencing, were not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but the authors postulated a toxic gain-of-function effect due to constitutive activation and abnormal GTPase signaling.
Scala et al. (2022) identified heterozygous mutations in the RAC3 gene in 10 unrelated patients with NEDBAF, including the patient with NEDBAF initially reported by White et al. (2018). Eight individual mutations were identified (see, e.g., 602050.0004-602050.0008) and all were shown to be de novo. When RAC3 with each of the mutations was expressed in cultures of primary mouse hippocampal neurons, the neurons displayed less neurite expression and rounding of the cell body compared to controls. The GDP/GTP exchange rate and GTP hydrolysis activity were tested in recombinant RAC3 with each mutation. The E62del, D63N, Y64C, K116N mutations resulted in higher GDP/GTP exchange activity compared to wildtype, but GTP hydrolysis activity of the Y64C and K116N mutants was similar to wildtype and the hydrolysis activity of the E62del mutant was lower than wildtype. The G12R, A59G, E62K mutations resulted in a similar GDP/GTP exchange activity compared to wildtype, but the G12R and A59G mutants had suppressed GTP-hydrolysis activity compared to wildtype. The G60D mutation resulted in a lower GDP/GTP exchange activity and a lower GTP hydrolysis rate compared to wildtype. Scala et al. (2022) concluded that biochemical differences among the mutants variously dysregulates RAC3 function in vivo with possible associated clinical implications.
Corbetta et al. (2009) generated Rac1 and Rac3 double-knockout mice by conditionally deleting Rac1 in neurons of Rac3 -/- mice due to lethality of Rac1 -/- mice. Double-knockout mice were smaller than controls, but brain weight was normal. Double-knockout mice had neurologic abnormalities with spontaneous seizures and died around postnatal day-13. Brains of mutant mice showed specific defects in dorsal hippocampal hilus that were associated with alterations in the formation of hippocampal circuitry. Analysis with hippocampal cultures revealed that Rac1 and Rac3 played a synergistic role in the formation of dendritic spines, and as a result, spine formation was strongly hampered in neurons lacking Rac1 and Rac3.
By analyzing Rac1 and Rac3 double-knockout mice, Vaghi et al. (2014) demonstrated that Rac1 and Rac3 were required for development of cortical and hippocampal GABAergic interneurons, as the number of parvalbumin (PV)-positive cells was reduced in hippocampus and cortex of mutant mice. Deletion of the Rac1 and Rac3 also caused a defect in maturation of PV-positive interneurons, indicating that Rac1 and Rac3 were also required for development of hippocampal and cortical inhibitory circuits. The decreased number of cortical migrating interneurons and their altered morphology indicated a role for Rac1 and Rac3 in regulating motility of cortical interneurons, thus interfering with their final localization. In addition, while electrophysiologic passive and active properties of pyramidal neurons, including membrane capacity, resting potential, and spike amplitude and duration, were normal, these cells showed reduced spontaneous inhibitory currents and increased excitability in mutant mice.
Scala et al. (2022) studied the effects of 4 RAC3 mutations located in the switch II region in patients with NEDBAF (Q61L, 602050.0002; E62del, 602050.0006; D63N, 602050.0005; Y64C, 602050.0007) in mouse embryos. RAC3 with each of the 4 mutations was electroporated into the ventricular zone of the brains at embryonic day 14.5. Each RAC3 mutation resulted in abnormal neuronal migration, with transfected neurons remaining in the ventricular and subventricular zones and in the intermediate zone. Scala et al. (2022) concluded that RAC3 plays a pivotal role in neuronal migration.
In a girl (BAB8740) with neurodevelopmental disorder with structural brain anomalies and dysmorphic facies (NEDBAF; 618577), White et al. (2018) identified a de novo heterozygous c.176C-G transversion (c.176C-G, NM_005052.2) in the RAC3 gene, resulting in an ala59-to-gly (A59G) substitution. The mutation was found by exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed.
In a 17-year-old boy of Caucasian descent (family I) with neurodevelopmental disorder with structural brain anomalies and dysmorphic facies (NEDBAF; 618577), Costain et al. (2019) identified a de novo heterozygous c.182A-T transversion (c.182A-T, NM_005052.2) in the RAC3 gene, resulting in a gln61-to-leu (Q61L) substitution at a conserved residue. The mutation, which was found by exome sequencing, was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed.
In a 5-year-old boy of Caucasian descent (family II) with neurodevelopmental disorder with structural brain anomalies and dysmorphic facies (NEDBAF; 618577), Costain et al. (2019) identified a de novo heterozygous c.86C-T transition (c.86C-T, NM_005052.2) in the RAC3 gene, resulting in a pro29-to-leu (P29L) substitution at a conserved residue. The mutation, which was found by exome sequencing, was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed.
In a 5-year-old boy of Caucasian descent (family III) and in 2 half sibs (family IV) with neurodevelopmental disorder with structural brain anomalies and dysmorphic facies (NEDBAF; 618577), Costain et al. (2019) identified a heterozygous c.184G-A transition (c.184G-A, NM_005052.2) in the RAC3 gene, resulting in a glu62-to-lys (E62K) substitution at a conserved residue. The mutation, which was found by exome sequencing, was not present in the gnomAD database. The mutation occurred de novo in the affected child from family III and was suspected to be gonadal mosaic in the unaffected mother from family IV. Functional studies of the variant and studies of patient cells were not performed.
In a patient (patient 7) with NEDBAF, Scala et al. (2022) identified heterozygosity for the E62K mutation in the RAC3 gene. The mutation was identified by next-generation sequencing of a panel of 480 genes associated with intellectual disability. The mutation was not present in the father and could not be tested in the mother because the patient was conceived via an egg donor. When RAC3 with the E62K mutation was expressed in cultures of primary mouse hippocampal neurons, the neurons displayed less neurite expression and rounding of the cell body compared to controls.
In 2 unrelated patients (patients 1 and 9) with neurodevelopmental disorder with structural brain anomalies and dysmorphic facies (NEDBAF; 618577), Scala et al. (2022) identified heterozygosity for a de novo c.187G-A transition (c.187G-A, NM_005052.3) in the RAC3 gene, resulting in an asp63-to-asn (D63N) substitution. The mutation, which was identified by trio whole-exome sequencing in patient 1 and with singleton whole-exome sequencing in patient 9, was confirmed by Sanger sequencing in both patients. When RAC3 with the D63N mutation was expressed in cultures of primary mouse hippocampal neurons, the neurons displayed less neurite expression and rounding of the cell body compared to controls.
In a patient (patient 2) with neurodevelopmental disorder with structural brain anomalies and dysmorphic facies (NEDBAF; 618577), Scala et al. (2022) identified heterozygosity for a de novo 3-bp deletion (c.186_188delGGA, NM_005052.3) in the RAC3 gene, resulting in a deletion of Glu62 (E62del). The mutation was identified by trio whole-exome sequencing and confirmed by Sanger sequencing. When RAC3 with the E62del mutation was expressed in cultures of primary mouse hippocampal neurons, the neurons displayed less neurite expression and rounding of the cell body compared to controls. Recombinant RAC3 with the E62del mutation had a higher rate of GTP/GDP exchange but a lower rate of GTP hydrolysis compared to wildtype.
In a patient (patient 3) with neurodevelopmental disorder with structural brain anomalies and dysmorphic facies (NEDBAF; 618577), Scala et al. (2022) identified heterozygosity for a de novo c.191A-G transition (c.191A-G, NM_005052.3) in the RAC3 gene, resulting a tyr64-to-cys (Y64C) substitution. The mutation was identified by trio whole-exome sequencing and confirmed by Sanger sequencing. When RAC3 with the Y64C mutation was expressed in cultures of primary mouse hippocampal neurons, the neurons displayed less neurite expression and rounding of the cell body compared to controls. Recombinant RAC3 with the Y64C mutation had a higher rate of GTP/GDP exchange compared to wildtype.
In 2 unrelated patients (patients 5 and 10) with neurodevelopmental disorder with structural brain anomalies and dysmorphic facies (NEDBAF; 618577), Scala et al. (2022) identified heterozygosity for a de novo c.34G-C transversion (c.34G-C, NM_005052.3) in the RAC3 gene, resulting a gly12-to-arg (G12R) substitution. The mutation was identified by trio whole-exome sequencing and confirmed by Sanger sequencing. When RAC3 with the G12R mutation was expressed in cultures of primary mouse hippocampal neurons, the neurons displayed less neurite expression and rounding of the cell body compared to controls.
Corbetta, S., Gualdoni, S., Ciceri, G., Monari, M., Zuccaro, E., Tybulewicz, V. L., de Curtis, I. Essential role of Rac1 and Rac3 GTPases in neuronal development. FASEB J. 23: 1347-1357, 2009. [PubMed: 19126596] [Full Text: https://doi.org/10.1096/fj.08-121574]
Costain, G., Callewaert, B., Gabriel, H., Tan, T. Y., Walker, S., Christodoulou, J., Lazar, T., Menten, B., Orkin, J., Sadedin, S., Snell, M., Vanlander, A., 9 others. Do novo missense variants in RAC3 cause a novel neurodevelopmental syndrome. Genet. Med. 21: 1021-1026, 2019. [PubMed: 30293988] [Full Text: https://doi.org/10.1038/s41436-018-0323-y]
Courjal, F., Chuchana, P., Theillet, C., Fort, P. Structure and chromosomal assignment to 22q12 and 17qter of the ras-related Rac2 and Rac3 human genes. Genomics 44: 242-246, 1997. [PubMed: 9299243] [Full Text: https://doi.org/10.1006/geno.1997.4871]
Haataja, L., Groffen, J., Heisterkamp, N. Characterization of RAC3, a novel member of the Rho family. J. Biol. Chem. 272: 20384-20388, 1997. [PubMed: 9252344] [Full Text: https://doi.org/10.1074/jbc.272.33.20384]
Morris, C. M., Haataja, L., McDonald, M., Gough, S., Markie, D., Groffen, J., Heisterkamp, N. The small GTPase RAC3 gene is located within chromosome band 17q25.3 outside and telomeric of a region commonly deleted in breast and ovarian tumours. Cytogenet. Cell Genet. 89: 18-23, 2000. [PubMed: 10894930] [Full Text: https://doi.org/10.1159/000015583]
Scala, M., Nishikawa, M., Ito, H., Tabata, H., Khan, T., Accogli, A., Davids, L., Ruiz, A., Chiurazzi, P., Cericola, G., Schulte, B., Monaghan, K. G., and 34 others. Variant-specific changes in RAC3 function disrupt corticogenesis in neurodevelopmental phenotypes. Brain 145: 3308-3327, 2022. [PubMed: 35851598] [Full Text: https://doi.org/10.1093/brain/awac106]
Vaghi, V., Pennucci, R., Talpo, F., Corbetta, S., Montinaro, V., Barone, C., Croci, L., Spaiardi, P., Consalez, G. G., Biella, G., de Curtis, I. Rac1 and rac3 GTPases control synergistically the development of cortical and hippocampal GABAergic interneurons. Cereb. Cortex 24: 1247-1258, 2014. [PubMed: 23258346] [Full Text: https://doi.org/10.1093/cercor/bhs402]
White, J. J., Mazzeu, J. F., Coban-Akdemir, Z., Bayram, Y., Bahrambeigi, V., Hoischen, A., van Bon, B. W. M., Gezdirici, A., Gulec, E. Y., Ramond, F., Touraine, R., Thevenon, J., and 24 others. WNT signaling perturbations underlie the genetic heterogeneity of Robinow syndrome. Am. J. Hum. Genet. 102: 27-43, 2018. [PubMed: 29276006] [Full Text: https://doi.org/10.1016/j.ajhg.2017.10.002]