Submicroscopic duplication in Xq28 causes increased expression of the MECP2 gene in a boy with severe mental retardation and features of Rett syndrome

Meins, Moritz

doi:10.1136/jmg.2004.023804

Cited by 208 publications

(216 citation statements)

References 26 publications

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“…21,22 MECP2 mutations are associated with a broad range of neurodevelopmental phenotypes that extend beyond classic Rett syndrome in females. We describe seven male patients with increased copy number of the MECP2 gene and surrounding loci on Xq28 identified by quantitative molecular testing and CMA in our diagnostic laboratory.…”

Section: Discussionmentioning

confidence: 99%

“…Submicroscopic Xq28 duplications containing the MECP2 gene with corresponding increase in RNA expression were reported in multiple male patients. 21,22 Those include one male who was duplicated for the entire MECP2 gene but not the flanking L1CAM gene. 21 In our study, the most severely affected patient is triplicated for the MECP2 gene.…”

Section: Discussionmentioning

confidence: 99%

“…13,19,20 More recent clinical testing for MECP2 gene rearrangements revealed that entire MECP2 gene duplications occur in some males manifesting a progressive neurodevelopmental syndrome. [21][22][23] Diagnostic studies at the Baylor Medical Genetics Laboratories have identified seven affected males with increased copynumber of the MECP2 gene. These include two males who were referred specifically for mutation analysis of the MECP2 gene and five males who were referred for microarray comparative genomic hybridization analysis for deletions or duplications of multiple genomic regions involved in clinical genomic disorders.…”

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Increased MECP2 gene copy number as the result of genomic duplication in neurodevelopmentally delayed males

Gaudio

Fang

Scaglia

et al. 2006

Genetics in Medicine

252

264

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Purpose: Mutations in the MECP2 gene are associated with Rett syndrome, an X-linked mental retardation disorder in females. Mutations also cause variable neurodevelopmental phenotypes in rare affected males. Recent clinical testing for MECP2 gene rearrangements revealed that entire MECP2 gene duplication occurs in some males manifesting a progressive neurodevelopmental syndrome. Methods: Clinical testing through quantitative DNA methods and chromosomal microarray analysis in our laboratories identified seven male patients with increased MECP2 gene copy number.Results: Duplication of the entire MECP2 gene was found in six patients, and MECP2 triplication was found in one patient with the most severe phenotype. The Xq28 duplications observed in these males are unique and vary in size from approximately 200 kb to 2.2 Mb. Three of the mothers who were tested were asymptomatic duplication carriers with skewed X-inactivation. In silico analysis of the Xq28 flanking region showed numerous low-copy repeats with potential roles in recombination. Conclusions: These collective data suggest that increased MECP2 gene copy number is mainly responsible for the neurodevelopmental phenotypes in these males. These findings underscore the allelic and phenotypic heterogeneity associated with the MECP2 gene and highlight the value of molecular analysis for patient diagnosis, family members at risk, and genetic counseling. Genet Med 2006:8(12):784-792.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Increased MECP2 gene copy number as the result of genomic duplication in neurodevelopmentally delayed males

Gaudio

Fang

Scaglia

et al. 2006

Genetics in Medicine

252

264

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“…The patients manifested several common phenotypes such as severe MR, muscular hypotonia, absence of speech and recurrent respiratory infections as reported. [15][16][17][18][19] Mapping at dup(X)(q28) of our three families indicated that the smallest region of overlap contained thirteen genes including L1CAM and MECP2 (Supplementary Figure S4a), suggesting that these genes contribute to their …”

Section: Detection Of Nine Benign Cnvsmentioning

confidence: 95%

Copy-number variations on the X chromosome in Japanese patients with mental retardation detected by array-based comparative genomic hybridization analysis

et al. 2010

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Mental Retardation Consortium 8X-linked mental retardation (XLMR) is a common, clinically complex and genetically heterogeneous disease arising from many mutations along the X chromosome. Although research during the past decade has identified 490 XLMR genes, many more remain uncharacterized. In this study, copy-number variations (CNVs) were screened in individuals with MR from 144 families by array-based comparative genomic hybridization (aCGH) using a bacterial artificial chromosome-based X-tiling array. Candidate pathogenic CNVs (pCNVs) were detected in 10 families (6.9%). Five of the families had pCNVs involving known XLMR genes, duplication of Xq28 containing MECP2 in three families, duplication of Xp11.22-p11.23 containing FTSJ1 and PQBP1 in one family, and deletion of Xp11.22 bearing SHROOM4 in one family. New candidate pCNVs were detected in five families as follows: identical complex pCNVs involved in dup(X)(p22.2) and dup(X)(p21.3) containing part of REPS2, NHS and IL1RAPL1 in two unrelated families, duplication of Xp22.2 including part of FRMPD4, duplication of Xq21.1 including HDX and deletion of Xq24 noncoding region in one family, respectively. Both parents and only mother samples were available in six and three families, respectively, and pCNVs were inherited from each of their mothers in those families other than a family of the proband with deletion of SHROOM4. This study should help to identify the novel XLMR genes and mechanisms leading to MR and reveal the clinical conditions and genomic background of XLMR.

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“…Loss-of-function mutations in MeCP2 lead to the severe pediatric neurological disorder, Rett syndrome (RTT) (3), which affects around one in 10,000 girls. In addition, extra copies of the gene cause MeCP2 duplication syndrome (4,5), a distinct intellectual disability disorder that predominantly affects males (6). The importance of MeCP2 for brain function has prompted investigation of its molecular function.…”

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Structure of the MeCP2–TBLR1 complex reveals a molecular basis for Rett syndrome and related disorders

Kruusvee

Lyst

Taylor

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Rett syndrome (RTT) is an X-linked neurological disorder caused by mutations in the methyl-CpG-binding protein 2 (MeCP2) gene. The majority of RTT missense mutations disrupt the interaction of the MeCP2 with DNA or the nuclear receptor corepressor (NCoR)/silencing mediator of retinoic acid and thyroid receptors (SMRT) corepressor complex. Here, we show that the "NCoR/SMRT interaction domain" (NID) of MeCP2 directly contacts transducin beta-like 1 (TBL1) and TBL1 related (TBLR1), two paralogs that are core components of NCoR/SMRT. We determine the cocrystal structure of the MeCP2 NID in complex with the WD40 domain of TBLR1 and confirm by in vitro and ex vivo assays that mutation of interacting residues of TBLR1 and TBL1 disrupts binding to MeCP2. Strikingly, the four MeCP2-NID residues mutated in RTT are those residues that make the most extensive contacts with TBLR1. Moreover, missense mutations in the gene for TBLR1 that are associated with intellectual disability also prevent MeCP2 binding. Our study therefore reveals the molecular basis of an interaction that is crucial for optimal brain function.T he methyl-CpG-binding protein 2 (MeCP2) is a chromatinassociated factor that is highly expressed in the brain (1, 2). Loss-of-function mutations in MeCP2 lead to the severe pediatric neurological disorder, Rett syndrome (RTT) (3), which affects around one in 10,000 girls. In addition, extra copies of the gene cause MeCP2 duplication syndrome (4, 5), a distinct intellectual disability disorder that predominantly affects males (6). The importance of MeCP2 for brain function has prompted investigation of its molecular function. The protein was identified because of its ability to bind DNA via its methyl-CpG-binding domain (MBD) (1, 7) and many residues mutated in RTT disrupt this interaction (8-11). In addition to DNA, numerous protein partners of MeCP2 have been reported (11). Of these protein partners, only the interactions with the nuclear receptor corepressor (NCoR) and its close relative silencing mediator of retinoic acid and thyroid receptors (SMRT) (12-14) are known to be disrupted by RTT missense mutations (13). Accordingly, Rett missense mutations outside the MBD are found clustered within the so-called "NCoR/SMRT interaction domain" (NID) (13) (Fig. 1A and Fig. S1A). One NID mutation, R306C, causes a severe RTT-like phenotype in mice (13,15,16). Moreover, mouse models of MeCP2 duplication syndrome suggest that both the MBD and the NID must be intact for this adverse molecular pathology to develop (16,17).These findings indicate that the NID mediates an essential function of MeCP2. This function may be recruitment of the NCoR/ SMRT corepressor complexes to chromatin. Alternatively, the NID may perform other essential roles, such as DNA binding, whose loss leads to RTT (16). In an attempt to distinguish among these possibilities, we investigated the molecular basis of the interaction between MeCP2 and NCoR/SMRT. The latter are ∼1.2-MDa multisubunit complexes that include NCoR1 (and/or SMRT), HDAC3, GPS2, and...

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Submicroscopic duplication in Xq28 causes increased expression of the MECP2 gene in a boy with severe mental retardation and features of Rett syndrome

Cited by 208 publications

References 26 publications

Increased MECP2 gene copy number as the result of genomic duplication in neurodevelopmentally delayed males

Increased MECP2 gene copy number as the result of genomic duplication in neurodevelopmentally delayed males

Copy-number variations on the X chromosome in Japanese patients with mental retardation detected by array-based comparative genomic hybridization analysis

Structure of the MeCP2–TBLR1 complex reveals a molecular basis for Rett syndrome and related disorders

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