Alternative titles; symbols
HGNC Approved Gene Symbol: PAK3
Cytogenetic location: Xq23 Genomic coordinates (GRCh38) : X:110,944,397-111,227,361 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xq23 | Intellectual developmental disorder, X-linked 30 | 300558 | X-linked recessive | 3 |
Ras (HRAS; 190020)-related GTPases, or p21 proteins, of the Rho (RHOA; 165390) subfamily are critical regulators of signal transduction pathways. The p21-activated kinases (PAKs) are a family of serine/threonine kinases that are central to signal transduction and cellular regulation. PAKs are involved in a variety of cellular processes, including cytoskeletal dynamics, cell motility, gene transcription, death and survival signaling, and cell cycle progression. Consequently, PAKs are implicated in numerous pathologic conditions and in cell transformation. The PAK family is divided into 2 subfamilies, group I and group II, based on domain architecture and regulation. Group I, the conventional PAKs, includes PAK1 (602590), PAK2 (605022), and PAK3, which are activated upon binding the GTP-bound forms of the Rho GTPases CDC42 (116952) and RAC1 (602048). Group II, the nonconventional PAKs, includes PAK4 (605451), PAK5 (PAK7; 608038), and PAK6 (608110), which are active independent of Rho GTPases (reviews by Zhao and Manser (2005) and Eswaran et al. (2008)).
By screening rat brain cytosol for proteins that interacted with Ras (HRAS; 190020)-related GTPases, or p21 proteins, of the Rho (RHOA; 165390) subfamily, Manser et al. (1994) identified 3 proteins that interacted with the GTP-bound forms of human CDC42 (116952) and RAC1 (602048), but not RHOA. Manser et al. (1995) isolated a rat cDNA encoding 1 of these proteins, Pak3. Bagrodia et al. (1995) cloned mouse Pak3.
Chelly (1999) referred to the PAK3 gene as oligophrenin-3 (OPHN3).
By Northern blot analysis of adult mouse tissues, Kohn et al. (2004) observed 3 isoforms of Pak3: a 2.2-kb testis-specific transcript, a 2.4-kb transcript expressed in brain and testis, and an approximately 3-kb transcript expressed in kidney and brain. In situ hybridization on mouse embryo sections showed that Pak3 was not expressed at early midgestational stages, showed its highest expression at the base of the diencephalon in the supraoptic area at embryonic day 11.5, and showed more expression in the subventricular zone at embryonic day 14.5.
Gross (2011) mapped the PAK3 gene to chromosome Xq23 based on an alignment of the PAK3 sequence (GenBank AF155651) with the genomic sequence (GRCh37).
In affected members of an Australian family with a form of nonsyndromic X-linked intellectual developmental disorder (XLID30; 300558) found by Donnelly et al. (1996) to map to chromosome Xq21.3-q24, Allen et al. (1998) identified a mutation in the PAK3 gene (300142.0001).
In affected members of a French family with XLID reported by des Portes et al. (1997), Bienvenu et al. (2000) identified a mutation in the PAK3 gene (300142.0002).
Huang et al. (2011) noted that knockout of either Pak1 or Pak3 in mice results in no overt abnormality. They found that double knockout (DK) of both Pak1 and Pak3 resulted in mice that were born healthy, with normal brain size and structure. However, postnatal brain growth in DK mice was severely impaired due to reduced neuronal cell volume, reduced axonal and dendritic branching, and reduced synaptic density. Behaviorally, DK mice were hyperactive and anxious, and they exhibited a learning deficit compared with wildtype mice. These structural and functional deficits in DK mice were associated with abnormal electrophysiologic activity in hippocampus and enhanced synaptic cofilin (see 601442) activity.
In affected males of an Australian family with nonsyndromic X-linked intellectual developmental disorder-30 (XLID30; 300558) reported by Donnelly et al. (1996), Allen et al. (1998) identified a 1255C-T transition in the PAK3 gene, resulting in an arg419-to-ter (R419X) substitution. The mutation was not identified in any unaffected males or more than 45 control individuals. When the MRX30 mutation was introduced into PAK3 cDNA and transfected into COS cells, the cDNA produced a stable, albeit truncated, protein with no measurable kinase activity. MRI studies of the more severely affected male with MRX30, who was microcephalic (although several other affected males were not), showed normal gross architecture of the cortex and hippocampus and other structures. Although more subtle defects in neuronal development could not be ruled out, MRI analysis suggested that PAK3 is not absolutely required for neuronal proliferation, migration, or cortical gyration. Therefore, the finding that the PAK3 mutation produces mental retardation may reflect a later requirement for PAK3 in axon outgrowth or function of the adult cortex.
In affected males of a French family with nonsyndromic X-linked intellectual developmental disorder-30 (XLID30; 300558) reported by des Portes et al. (1997), Bienvenu et al. (2000) identified a 199C-T transition in exon 2 of the PAK3 gene, resulting in an arg67-to-cys (R67C) substitution in a polybasic region upstream of the CDC42/Rac interactive binding domain, and was predicted to affect GTPase binding.
In affected males of an Australian family with nonsyndromic X-linked intellectual developmental disorder-30 (XLID30; 300558), Gedeon et al. (2003) identified a 1094C-A transversion in exon 10 of the PAK3 gene, resulting in an ala365-to-glu (A365E) substitution. Affected males had borderline to mild mental retardation and most were able to function independently and hold menial jobs. Several patients had psychiatric disorders and some had relatively long ears. All carrier women had normal intelligence.
In 5 males with intellectual developmental disorder-30 (XLID30; 300558) in a Finnish family, Peippo et al. (2007) identified a 1337G-C transversion in exon 7 of the PAK3 gene, resulting in a trp446-to-ser (W446S) substitution. Each mother of an affected male was found to be a carrier of the mutation. Peippo et al. (2007) examined X inactivation in carrier females by the methylation status of the polymorphic AR locus (313700). Skewed X inactivation was identified in 2 phenotypically normal females (90%:10%; 91%:9%) as well as in a borderline retarded female (100%:0%). The mutation was not found in 2 male relatives or in 200 unrelated Finnish controls.
In 3 affected males from a Tunisian family with X-linked intellectual developmental disorder-30 (XLID30; 300558), Rejeb et al. (2008) identified an A-to-G transition (276+4G-A) in intron 6 of the PAK3 gene, predicted to result in a novel donor splice site. RT-PCR analysis of patient RNA showed that the mutation resulted in a 4-bp insertion, frameshift, and premature termination at codon 128. The mutation was not identified in 200 control individuals. The phenotype was homogeneous, with microcephaly, oral motor dysfunction, and behavioral disturbances. X-inactivation studies showed completely skewed X inactivation in 2 female carriers.
Allen, K. M., Gleeson, J. G., Bagrodia, S., Partington, M. W., MacMillan, J. C., Cerione, R. A., Mulley, J. C., Walsh, C. A. PAK3 mutation in nonsyndromic X-linked mental retardation. Nature Genet. 20: 25-30, 1998. [PubMed: 9731525] [Full Text: https://doi.org/10.1038/1675]
Bagrodia, S., Taylor, S. J., Creasy, C. L., Chernoff, J., Cerione, R. A. Identification of a mouse p21Cdc/Rac activated kinase. J. Biol. Chem. 270: 22731-22737, 1995. Note: Erratum: J. Biol. Chem. 271: 1250 only, 1996. [PubMed: 7559398] [Full Text: https://doi.org/10.1074/jbc.270.39.22731]
Bienvenu, T., des Portes, V., McDonell, N., Carrie, A., Zemni, R., Couvert, P., Ropers, H. H., Moraine, C., van Bokhoven, H., Fryns, J. P., Allen, K., Walsh, C. A., Boue, J., Kahn, A., Chelly, J., Beldjord, C. Missense mutation in PAK3, R67C, causes X-linked nonspecific mental retardation. Am. J. Med. Genet. 93: 294-298, 2000. [PubMed: 10946356] [Full Text: https://doi.org/10.1002/1096-8628(20000814)93:4<294::aid-ajmg8>3.0.co;2-f]
Chelly, J. Breakthroughs in molecular and cellular mechanisms underlying X-linked mental retardation. Hum. Molec. Genet. 8: 1833-1838, 1999. [PubMed: 10469834] [Full Text: https://doi.org/10.1093/hmg/8.10.1833]
des Portes, V., Soufir, N., Carrie, A., Billuart, P., Bienvenu, T., Vinet, M. C., Beldjord, C., Ponsot, G., Kahn, A., Boue, J., Chelly, J. Gene for nonspecific X-linked mental retardation (MRX 47) is located in Xq22.3-q24. Am. J. Med. Genet. 72: 324-328, 1997. [PubMed: 9332663] [Full Text: https://doi.org/10.1002/(sici)1096-8628(19971031)72:3<324::aid-ajmg14>3.0.co;2-v]
Donnelly, A. J., Partington, M. W., Ryan, A. K., Mulley, J. C. Regional localisation of two non-specific X-linked mental retardation genes (MRX30 and MRX31). Am. J. Med. Genet. 64: 113-120, 1996. [PubMed: 8826460] [Full Text: https://doi.org/10.1002/(SICI)1096-8628(19960712)64:1<113::AID-AJMG19>3.0.CO;2-Q]
Eswaran, J., Soundararajan, M., Kumar, R., Knapp, S. UnPAKing the class differences among p21-activated kinases. Trends Biochem. Sci. 33: 394-403, 2008. [PubMed: 18639460] [Full Text: https://doi.org/10.1016/j.tibs.2008.06.002]
Gedeon, A. K., Nelson, J., Gecz, J., Mulley, J. C. X-linked mild non-syndromic mental retardation with neuropsychiatric problems and the missense mutation A365E in PAK3. Am. J. Med. Genet. 120A: 509-517, 2003. [PubMed: 12884430] [Full Text: https://doi.org/10.1002/ajmg.a.20131]
Gross, M. B. Personal Communication. Baltimore, Md. 5/9/2011.
Huang, W., Zhou, Z., Asrar, S., Henkelman, M., Xie, W., Jia, Z. p21-activated kinases 1 and 3 control brain size through coordinating neuronal complexity and synaptic properties. Molec. Cell. Biol. 31: 388-403, 2011. [PubMed: 21115725] [Full Text: https://doi.org/10.1128/MCB.00969-10]
Kohn, M., Steinbach, P., Hameister, H., Kehrer-Sawatzki, H. A comparative expression analysis of four MRX genes regulating intracellular signalling via small GTPases. Europ. J. Hum. Genet. 12: 29-37, 2004. [PubMed: 14673471] [Full Text: https://doi.org/10.1038/sj.ejhg.5201085]
Manser, E., Chong, C., Zhao, Z. S., Leung, T., Michael, G., Hall, C., Lim, L. Molecular cloning of a new member of the p21-Cdc42/Rac-activated kinase (PAK) family. J. Biol. Chem. 270: 25070-25078, 1995. [PubMed: 7559638] [Full Text: https://doi.org/10.1074/jbc.270.42.25070]
Manser, E., Leung, T., Salihuddin, H., Zhao, Z., Lim, L. A brain serine/threonine protein kinase activated by Cdc42 and Rac1. Nature 367: 40-46, 1994. [PubMed: 8107774] [Full Text: https://doi.org/10.1038/367040a0]
Peippo, M., Koivisto, A. M., Sarkamo, T., Sipponen, M., von Koskull, H., Ylisaukko-oja, T., Rehnstrom, K., Froyen, G., Ignatius, J., Jarvela, I. PAK3 related mental disability: further characterization of the phenotype. Am. J. Med. Genet. 143A: 2406-2416, 2007. [PubMed: 17853471] [Full Text: https://doi.org/10.1002/ajmg.a.31956]
Rejeb, I., Saillour, Y., Castelnau, L., Julien, C., Bienvenu, T., Taga, P., Chaabouni, H., Chelly, J., Jemaa, L. B., Bahi-Buisson, N. A novel splice mutation in PAK3 gene underlying mental retardation with neuropsychiatric features. Europ. J. Hum. Genet. 16: 1358-1363, 2008. [PubMed: 18523455] [Full Text: https://doi.org/10.1038/ejhg.2008.103]
Zhao, Z., Manser, E. PAK and other Rho-associated kinases--effectors with surprisingly diverse mechanisms of regulation. Biochem. J. 386: 201-214, 2005. [PubMed: 15548136] [Full Text: https://doi.org/10.1042/BJ20041638]