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. 1998 Apr;35(4):284–287. doi: 10.1136/jmg.35.4.284

Genetic localisation of mental retardation with spastic diplegia to the pericentromeric region of the X chromosome: X inactivation in female carriers.

F Martínez 1, M Tomás 1, J M Millán 1, A Fernández 1, F Palau 1, F Prieto 1
PMCID: PMC1051274  PMID: 9598720

Abstract

We report on two brothers and one maternal cousin with severe mental retardation, microcephaly, short stature, cryptorchidism, and spastic diplegia. The patients were born to normal and non-consanguineous parents. All other members of the family, almost exclusively females, were clinically normal, suggesting X linked inheritance. By multipoint linkage analysis with markers spanning the whole X chromosome, we have tentatively assigned the underlying genetic defect to Xp11.4-q21, achieving a maximum lod score of 1.3. This localisation overlaps MRXS3, a syndromic form of mental retardation resembling that found in the family described here, although with a milder presentation. We discuss the possibility that both phenotypes might be allelic variants of the same gene localised in the pericentromeric region of the X chromosome. Analysis of the X inactivation pattern in one potential and three obligate carrier females showed non-random inactivation of the allele linked to the disease. This finding may be interpreted as: (1) a negative selection effect on cells bearing the mutation on the active X chromosome; (2) both the disease causing gene and the X inactivation centre are simultaneously affected by the same alteration, a deletion for instance; or (3) the skewed inactivation is the consequence of an independent event randomly associated with the disease. In any case, the observation of consistent X inactivation supports X linkage of the disease.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Allen R. C., Zoghbi H. Y., Moseley A. B., Rosenblatt H. M., Belmont J. W. Methylation of HpaII and HhaI sites near the polymorphic CAG repeat in the human androgen-receptor gene correlates with X chromosome inactivation. Am J Hum Genet. 1992 Dec;51(6):1229–1239. [PMC free article] [PubMed] [Google Scholar]
  2. Beidler J. L., Hilliard P. R., Rill R. L. Ultrasensitive staining of nucleic acids with silver. Anal Biochem. 1982 Nov 1;126(2):374–380. doi: 10.1016/0003-2697(82)90530-9. [DOI] [PubMed] [Google Scholar]
  3. Black G. C., Chen Z. Y., Craig I. W., Powell J. F. Dinucleotide repeat polymorphism at the MAOA locus. Nucleic Acids Res. 1991 Feb 11;19(3):689–689. doi: 10.1093/nar/19.3.689-a. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Clemens P. R., Fenwick R. G., Chamberlain J. S., Gibbs R. A., de Andrade M., Chakraborty R., Caskey C. T. Carrier detection and prenatal diagnosis in Duchenne and Becker muscular dystrophy families, using dinucleotide repeat polymorphisms. Am J Hum Genet. 1991 Nov;49(5):951–960. [PMC free article] [PubMed] [Google Scholar]
  5. Edwards A., Hammond H. A., Jin L., Caskey C. T., Chakraborty R. Genetic variation at five trimeric and tetrameric tandem repeat loci in four human population groups. Genomics. 1992 Feb;12(2):241–253. doi: 10.1016/0888-7543(92)90371-x. [DOI] [PubMed] [Google Scholar]
  6. Fain P. R., Kort E. N., Chance P. F., Nguyen K., Redd D. F., Econs M. J., Barker D. F. A 2D crossover-based map of the human X chromosome as a model for map integration. Nat Genet. 1995 Mar;9(3):261–266. doi: 10.1038/ng0395-261. [DOI] [PubMed] [Google Scholar]
  7. Fransen E., Vits L., Van Camp G., Willems P. J. The clinical spectrum of mutations in L1, a neuronal cell adhesion molecule. Am J Med Genet. 1996 Jul 12;64(1):73–77. doi: 10.1002/(SICI)1096-8628(19960712)64:1<73::AID-AJMG11>3.0.CO;2-P. [DOI] [PubMed] [Google Scholar]
  8. Gedeon A. K., Holman K., Richards R. I., Mulley J. C. Characterization of new PCR based markers for mapping and diagnosis: AC dinucleotide repeat markers at the DXS237 (GMGX9) and DXS102 (cX38.1) loci. 1992 Apr 15-May 1Am J Med Genet. 43(1-2):255–260. doi: 10.1002/ajmg.1320430140. [DOI] [PubMed] [Google Scholar]
  9. Gedeon A., Mulley J., Haan E. Gene localisation for Sutherland-Haan syndrome (SHS:MIM 309470) Am J Med Genet. 1996 Jul 12;64(1):78–79. doi: 10.1002/(SICI)1096-8628(19960712)64:1<78::AID-AJMG12>3.0.CO;2-P. [DOI] [PubMed] [Google Scholar]
  10. Gyapay G., Morissette J., Vignal A., Dib C., Fizames C., Millasseau P., Marc S., Bernardi G., Lathrop M., Weissenbach J. The 1993-94 Généthon human genetic linkage map. Nat Genet. 1994 Jun;7(2 Spec No):246–339. doi: 10.1038/ng0694supp-246. [DOI] [PubMed] [Google Scholar]
  11. Kirchgessner C. U., Trofatter J. A., Mahtani M. M., Willard H. F., DeGennaro L. J. A highly polymorphic dinucleotide repeat on the proximal short arm of the human X chromosome: linkage mapping of the synapsin I/A-raf-1 genes. Am J Hum Genet. 1991 Jul;49(1):184–191. [PMC free article] [PubMed] [Google Scholar]
  12. Lathrop G. M., Lalouel J. M. Easy calculations of lod scores and genetic risks on small computers. Am J Hum Genet. 1984 Mar;36(2):460–465. [PMC free article] [PubMed] [Google Scholar]
  13. Lubs H. A., Chiurazzi P., Arena J. F., Schwartz C., Tranebjaerg L., Neri G. XLMR genes: update 1996. Am J Med Genet. 1996 Jul 12;64(1):147–157. doi: 10.1002/(SICI)1096-8628(19960712)64:1<147::AID-AJMG25>3.0.CO;2-M. [DOI] [PubMed] [Google Scholar]
  14. Luty J. A., Guo Z., Willard H. F., Ledbetter D. H., Ledbetter S., Litt M. Five polymorphic microsatellite VNTRs on the human X chromosome. Am J Hum Genet. 1990 Apr;46(4):776–783. [PMC free article] [PubMed] [Google Scholar]
  15. Naumova A. K., Plenge R. M., Bird L. M., Leppert M., Morgan K., Willard H. F., Sapienza C. Heritability of X chromosome--inactivation phenotype in a large family. Am J Hum Genet. 1996 Jun;58(6):1111–1119. [PMC free article] [PubMed] [Google Scholar]
  16. Schäffer A. A., Gupta S. K., Shriram K., Cottingham R. W., Jr Avoiding recomputation in linkage analysis. Hum Hered. 1994 Jul-Aug;44(4):225–237. doi: 10.1159/000154222. [DOI] [PubMed] [Google Scholar]
  17. Sutherland G. R., Gedeon A. K., Haan E. A., Woodroffe P., Mulley J. C. Linkage studies with the gene for an X-linked syndrome of mental retardation, microcephaly and spastic diplegia (MRX2) Am J Med Genet. 1988 May-Jun;30(1-2):493–508. doi: 10.1002/ajmg.1320300152. [DOI] [PubMed] [Google Scholar]
  18. Wehnert M., Reiner O., Caskey C. T. Four STR polymorphisms map to a 500 kb region between DXS15 and DXS134. Hum Mol Genet. 1993 Sep;2(9):1503–1503. doi: 10.1093/hmg/2.9.1503. [DOI] [PubMed] [Google Scholar]

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