Mutational Analysis of the MECP2 Gene in Tunisian Patients With Rett Syndrome: A Novel Double Mutation

Abstract

Rett syndrome is a severe disorder characterized by loss of acquired skills after a period of normal development in infant girls. It is caused mainly by mutations in the MECP2 gene. In this study, we reported mutations in the MECP2 gene in 7 Tunisian patients with classic Rett syndrome. The results showed the presence of a double mutation in 1 patient: p.R306C and c.1461+98insA, which create a new hypothetical polyadenylation site in the 3^′UTR of the MECP2 gene. We also detected in another patient a new variant c.1461+92C>G in the 3^′UTR located previous to 34 bp from the polyadenylation site with a score of 4.085. This variation is located in a hypothetical splicing enhancer with a score of 1.96277 according to the ESE finder program. In the remaining 5 patients, we found 2 common mutations: p.T158M in 4 individuals and p.R168X in only 1 girl.

Keywords

Rett syndrome double-mutation MECP2 gene T158M R168X R306C 3′UTR polyadenylation site

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References

Hagberg B. , Hagberg G. Rett syndrome: epidemiology and geographical variability. Eur Child Adolesc Psychiatry. 1997;6(Suppl 1): 5-7.

Hagberg B. , Aicardi J. , Dias K. , Ramos O. A progressive syndrome of autism, dementia, ataxia, and loss of purposeful hand use in girls: Rett’s syndrome. Report of 35 cases. Ann Neurol. 1983;14: 471-479.

Xiang F. , Stenbom Y. , Anvret M. , Hagberg B. Closely related Swedish Rett syndrome females: none with MECP2 mutation revealed . Neuropediatrics. 2001;32:217-218.

Amir RE , Van Den Veyver IB , Wan M. , et al. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpGbinding protein 2. Nat Genet. 1999 ;23:185-188.

Harikrishnan KN , Chow MZ , Baker EK , et al. Brahma links the SWI/SNF chromatin-remodeling complex with MeCP2dependent transcriptional silencing. Nat Genet. 2005;37:254-264.

Nan X. , Bird A. The biological functions of the methyl-CpGbinding protein MeCP2 and its implication in Rett syndrome. Brain Dev. 2001;23:S32-S37.

Matijevic T. , Knezevic J. , Slavica M. , Pavelic J. Rett syndrome: from the gene to the disease . Eur Neurol. 2009;61(1):3-10.

Wan M. , Lee SSJ , Zhang X. Rett syndrome and beyond: recurrent spontaneous and familial MECP2 mutations at CpG hotspots. Am J Hum Genet. 1999;65:1520-1529.

Fukuda T. , Yamashita Y. , Nagamitsu S. , et al. Methyl-CpG binding protein 2 gene (MECP2) variations in Japanese patients with Rett syndrome: pathological mutations and polymorphisms. Brain Dev. 2005;27:211-217.

10.

Matijević T. , Knezević J. , Barisić I. , et al. The MECP2 gene mutation screening in Rett syndrome patients from Croatia. Ann N Y Acad Sci. 2006;1091:225-232.

11.

Fendri-Kriaa N. , Abdelkafi Z. , Rebeh I. , et al. A novel MECP2 gene mutation in a Tunisian patient with Rett syndrome. Genet Test Mol Biomarkers. 2009;13:109-113.

12.

Lewin HA , Stewart-Haynes JA , A simple method for DNA extraction from leukocytes for use in PCR . Biotechniques. 1992;13:522-524.

13.

Bourdon V. , Philippe C. , Labrune O. , et al. A detailed analysis of the MECP2 gene: prevalence of recurrent mutations and gross DNA rearrangements in Rett syndrome patients. Hum Genet. 2001;108:43-50.

14.

Santos M. , Yan J. , Temudo T. Analysis of highly conserved regions of the 3′ UTR of MECP2 gene in patients with clinical diagnosis of Rett syndrome and other disorders associated with mental retardation. Dis Markers. 2008 ;24:319-324.

15.

Bienvenu T. , Chelly J. Molecular genetics of Rett syndrome: when DNA methylation goes unrecognized. Nat Rev Genet. 2006;7:415-426.

16.

Weaving LS , Williamson SL , Bennetts B. , et al. Effects of MECP2 mutation type, location and X-inactivation in modulating Rett syndrome phenotype. Am J Med Genet. 2003;118A:103-114.

17.

Bunyan DJ , Robinson DO Multiple de novo mutations in the MECP2 gene. Genet Test. 2008;12:373-375.

18.

Zahorakova D. , Rosipal R. , Hadac J. Mutation analysis of the MECP2 gene in patients of Slavic origin with Rett syndrome: novel mutations and polymorphisms. J Hum Genet. 2007;52:342-348.

19.

Coutinho AM , Oliveira G. , Katz C. , et al. MECP2 coding sequence and 3′UTR variation in 172 unrelated autistic patients. Am J Med Genet B Neuropsychiatr Genet. 2007;4:475-483.