Alternative titles; symbols
ORPHA: 777; DO: 0112051;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Xq23 | Intellectual developmental disorder, X-linked 30 | 300558 | X-linked recessive | 3 | PAK3 | 300142 |
A number sign (#) is used with this entry because of evidence that nonsyndromic X-linked intellectual developmental disorder-30 (XLID30) is caused by mutation in the gene encoding p21-activated kinase-3 (PAK3; 300142) on chromosome Xq23.
Des Portes et al. (1997) reported a French family in which 6 males in 2 generations had nonsyndromic X-linked mental retardation. All affected males had moderate to severe mental retardation without seizures, statural growth deficiencies, or other physical abnormalities.
Gedeon et al. (2003) reported an Australian family with nonsyndromic MRX affecting 19 males in 5 generations. Some of the patients had relatively long ears, but no other physical abnormalities. The mental deficit was borderline to mild, and most attended special schools, had menial jobs, and could perform activities of daily living independently. Four patients had histories of psychiatric problems, including features of schizophrenia. Carrier females had no abnormalities.
Peippo et al. (2007) further characterized PAK3-related mental retardation in a Finnish family. The 5 affected males examined had a proportionately small head or microcephaly, large ears, thin upper lip, open mouth appearance, drooling, and inarticulate speech. Behavioral features included short attention span, anxiety, restlessness, and aggression. One affected male had paranoid psychosis. EEG recordings in 4 affected males and 1 carrier female demonstrated similar posterior slow wave activity without epileptic discharge. One affected male had epilepsy. Neuropsychologic testing in affected males and carrier females suggested a common profile of impaired spatial cognitive abilities and defects in attentional and executive functions. In contrast to the report by Gedeon et al. (2003), most carrier females manifested learning problems and mild mental disability. Skewed X-inactivation was observed in female carriers.
Rejeb et al. (2008) reported a Tunisian family with PAK3-related mental retardation. The phenotype was relatively homogeneous and characterized by microcephaly, marked hypotonia, and oromotor dysfunction with drooling and speech difficulties. Affected individuals also had characteristic behavioral features, including aggression, hyperactivity, and agitation. Dysmorphic features consisted of microcephaly, flat face, low forehead, upslanting palpebral fissures, short nose with upturned nasal tips, large ears, large open mouth, and high palate. The findings suggested a specific phenotype.
By linkage analysis of an Australian family with mental retardation, Donnelly et al. (1996) identified a candidate locus, termed MRX30, within a 28-cM region on chromosome Xq21.3-q24 between markers DXS990 and DXS424 (maximum multipoint lod score of 2.78).
By linkage analysis of a French family with nonsyndromic X-linked mental retardation, des Portes et al. (1997) identified a candidate disease locus, termed MRX47, on chromosome Xq22.3-q24 (maximum 2-point lod score of 3.75 at marker DXS1059). Recombination events defined a 17-cM interval between DXS1105 and DXS8067. The region overlapped with that reported by Donnelly et al. (1996) for MRX30.
Allen et al. (1998) identified a mutation in the PAK3 gene (300142.0001) in affected males of the Australian family with MRX30 reported by Donnelly et al. (1996).
In affected members of the French family with MRX47 reported by des Portes et al. (1997), Bienvenu et al. (2000) identified a mutation in the PAK3 gene (300142.0002).
Gedeon et al. (2003) identified a mutation in the PAK3 gene (300142.0003) that segregated with mental retardation in an Australian family.
In 5 males with mental retardation in a Finnish family, Peippo et al. (2007) identified a novel missense mutation in the PAK3 gene (300142.0004). The mutation was absent in 2 unaffected male relatives. Each mother of an affected male was found to be a carrier of the mutation.
Rejeb et al. (2008) identified a mutation in the PAK3 gene (300142.0005) in affected members of a Tunisian family with mental retardation.
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]
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]
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]
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]
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]