Alternative titles; symbols
ORPHA: 276630, 777; DO: 0112019;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Xp22.12 | Intellectual developmental disorder, X-linked 19 | 300844 | X-linked dominant | 3 | RPS6KA3 | 300075 |
A number sign (#) is used with this entry because of evidence that X-linked intellectual developmental disorder-19 (XLID19) is caused by mutation in the RPS6KA3 gene (300075) on chromosome Xp22.
X-linked intellectual development disorder-19 (XLID19) is characterized by mildly to moderately impaired intellectual development. Carrier females may be mildly affected. Mutation in the RPS6KA3 gene also causes Coffin-Lowry syndrome (CLS; 303600), a syndrome with impaired intellectual deveopment, dysmorphic facial features, and skeletal anomalies. Some patients with RPS6KA3 mutations have an intermediate phenotype with impaired intellectual development and only mild anomalies reminiscent of CLS. These individuals have mutations resulting in some residual protein function, which likely explains the milder phenotype (summary by Field et al., 2006).
Choo et al. (1984) reported a family with nonsyndromic X-linked mental retardation that did not show linkage to fragile X syndrome (300624) or to the F9 (300746) gene on chromosome Xq27.
Donnelly et al. (1994) reported follow-up on the family reported by Choo et al. (1984), which now included affected members from 4 generations. Affected boys had moderate mental retardation but no distinctive characteristics, no physical anomalies, and no specific neurologic disturbances. Three females were reported to be mildly retarded.
Merienne et al. (1999) restudied the family reported by Choo et al. (1984) and Donnelly et al. (1994). Two affected individuals, then 38 and 29 years old, had none of the facial, digital, or skeletal features or the abnormal posture or gait typical of Coffin-Lowry syndrome. Furthermore, both presented with very mild mental retardation, compatible with social autonomy.
Clinical Variability
Field et al. (2006) reported 2 unrelated families with a clinical diagnosis of nonsyndromic X-linked mental retardation who were found to carry mutations in the RPS6KA3 gene. In 1 family, patients had coarse facial features, kyphoscoliosis, and some redundancy of palmar skin with horizontal creases, but no digital tapering or short stature. In the second family, the patients had short stature, hypertelorism, and a slightly full lower lip. However, in both families, these additional features were considered to be too mild for a diagnosis of Coffin-Lowry syndrome. Field et al. (2006) also reported affected males from a family in which CLS had been suspected based on coarse facial features and scoliosis in 1 of the males examined; however, the clinical features were considered atypical due to absence of significant scoliosis or digital changes in many of the affected males, and the intellectual disability was only mild to moderate.
By linkage analysis of a family with X-linked mental retardation (Choo et al., 1984), Donnelly et al. (1994) found linkage to a 42-cM interval on chromosome Xp22 (Zmax of 3.58 at markers DXS207 and DXS987, and Zmax of 3.28 at DXS999). The locus was designated MRX19. The authors noted that 2 additional syndromic mental retardation syndromes, Coffin-Lowry and Partington syndrome (PRTS; 309510), also map to this region, suggesting that they may represent the same entity.
In affected members of the MRX19 family reported by Choo et al. (1984) and Donnelly et al. (1994), Merienne et al. (1999) identified a mutation in the RPS6KA3 gene (R383W; 300075.0010). The R383W-mutant protein was notable in that the 5- to 6-fold decrease in kinase activity resulted in a milder phenotype compared to that observed in Coffin-Lowry syndrome. The findings demonstrated that 15 to 20% of RPS6KA3 activity is sufficient for normal signaling of the MAPK-RPS6KA3 pathway involved in skeletal development. Mutations in the RPS6KA3 gene were excluded from 2 additional families with nonspecific MRX (MRX2; 300428 and MRX21; 300143) mapping to the same region.
Field et al. (2006) identified 3 different mutations in the RPS6KA3 gene (see, e.g., 300075.0020-300075.0021) in affected members of 3 different families with nonsyndromic X-linked mental retardation. All 3 mutations affected the serine/threonine protein kinase domain, and Field et al. (2006) hypothesized that the mutant proteins had a small amount of residual activity, which likely explained the relatively mild phenotype.
Field et al. (2006) noted that the mutations in their report and the mutation (300075.0011) reported by Manouvrier-Hanu et al. (1999) in a family with mild Coffin-Lowry syndrome were small in-frame deletions or missense mutations affecting the serine/threonine kinase domain. Field et al. (2006) hypothesized that the presence of a small amount of residual enzymatic activity may be sufficient to maintain normal osteoblast differentiation and ameliorate the skeletal phenotype associated with CLS. The level of residual enzymatic activity has also been linked to cognitive performance, with higher levels being associated with a higher level of intellectual function (Harum et al., 2001).
Choo, K. H., George, D., Fillby, G., Halliday, J. L., Leversha, M., Webb, G., Danks, D. M. Linkage analysis of X-linked mental retardation with and without fragile-X using factor IX gene probe. (Letter) Lancet 324: 349 only, 1984. Note: Originally Volume II. [PubMed: 6146889] [Full Text: https://doi.org/10.1016/s0140-6736(84)92715-6]
Donnelly, A. J., Choo, K. H. A., Kozman, H. M., Gedeon, A. K., Danks, D. M., Mulley, J. C. Regional localisation of a non-specific X-linked mental retardation gene (MRX19) to Xp22. Am. J. Med. Genet. 51: 581-585, 1994. [PubMed: 7943043] [Full Text: https://doi.org/10.1002/ajmg.1320510457]
Field, M., Tarpey, P., Boyle, J., Edkins, S., Goodship, J., Luo, Y., Moon, J., Teague, J., Stratton, M. R., Futreal, P. A., Wooster, R., Raymond, F. L., Turner, G. Mutations in the RSK2(RPS6KA3) gene cause Coffin-Lowry syndrome and nonsyndromic X-linked mental retardation. Clin. Genet. 70: 509-515, 2006. [PubMed: 17100996] [Full Text: https://doi.org/10.1111/j.1399-0004.2006.00723.x]
Harum, K. H., Alemi, L., Johnston, M. V. Cognitive impairment in Coffin-Lowry syndrome correlates with reduced RSK2 activation. Neurology 56: 207-214, 2001. [PubMed: 11160957] [Full Text: https://doi.org/10.1212/wnl.56.2.207]
Manouvrier-Hanu, S., Amiel, J., Jacquot, S., Merienne, K., Moerman, A., Coeslier, A., Labarriere, F., Vallee, L., Croquette, M. F., Hanauer, A. Unreported RSK2 missense mutation in two male sibs with an unusually mild form of Coffin-Lowry syndrome. J. Med. Genet. 36: 775-778, 1999. [PubMed: 10528858] [Full Text: https://doi.org/10.1136/jmg.36.10.775]
Merienne, K., Jacquot, S., Pannetier, S., Zeniou, M., Bankier, A., Gecz, J., Mandel, J.-L., Mulley, J., Sassone-Corsi, P., Hanauer, A. A missense mutation in RPS6KA3 (RSK2) responsible for non-specific mental retardation. (Letter) Nature Genet. 22: 13-14, 1999. [PubMed: 10319851] [Full Text: https://doi.org/10.1038/8719]