XLMR syndrome characterized by multiple respiratory infections, hypertelorism, severe CNS deterioration and early death localizes to distal Xq28

Lubs, Herbert A.; Abidi, Fatima; Bier, Jo-Ann Blaymore; Abuelo, Diane; Ouzts, Lisbeth; Voeller, Kytja K. S.; Fennell, Eileen B.; Stevenson, Roger E.; Schwartz, Charles E.; Arena, Fernando

doi:10.1002/(sici)1096-8628(19990730)85:3<243::aid-ajmg11>3.0.co;2-e

Cited by 61 publications

(60 citation statements)

References 6 publications

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“…The genetically related Lubs syndrome (OMIM #300260) was first described in 1999, and etiologically resolved in 2005 as the MECP2 duplication syndrome. [4][5][6] Xq28 duplications of different sizes spanning the MECP2 gene have been identified to date as a common cause of mental retardation in males. In familial cases with X-linked pedigrees, the asymptomatic female carriers show a significant skewing of X-inactivation (XCI).…”

Section: Introductionmentioning

confidence: 99%

De novo MECP2 duplication in two females with random X-inactivation and moderate mental retardation

et al. 2011

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Xq28 duplications including MECP2 are a well-known cause of severe mental retardation in males with seizures, muscular hypotonia, progressive spasticity, poor speech and recurrent infections that often lead to early death. Female carriers usually show a normal intellectual performance due to skewed X-inactivation (XCI). We report on two female patients with a de novo MECP2 duplication associated with moderate mental retardation. In both patients, the de novo duplication occurred on the paternal allele, and both patients show a random XCI, which can be assumed as the triggering factor for the phenotype. Furthermore, we describe the phenotype that might be restricted to unspecific mild-to -moderate mental retardation with neurological features in early adulthood.

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Section: Introductionmentioning

confidence: 99%

De novo MECP2 duplication in two females with random X-inactivation and moderate mental retardation

et al. 2011

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“…In our screen of a large cohort of patients with X-linked mental retardation (XLMR) by full coverage Xchromosome-specific array-CGH (Froyen et al 2007) and realtime quantitative PCR (qPCR), we identified small duplications at Xq28 in four unrelated male patients with severe to profound mental retardation and additional clinical features , referred to as the Lubs X-linked mental retardation syndrome (XLMRL; OMIM 300260) (http://www.ncbi.nlm.nih. gov/omim/) (Lubs et al 1999). Delineation of the minimal critical region and detection of a twofold increased expression of MECP2 mRNA in the patient-derived cell lines compared with controls pointed to an increased dosage of MECP2 as the cause of the MR phenotype, thereby demonstrating a new disease mechanism in mental retardation .…”

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confidence: 98%

Nonrecurrent MECP2 duplications mediated by genomic architecture-driven DNA breaks and break-induced replication repair

Bauters¹,

Esch²,

Friez³

et al. 2008

Genome Res.

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122

124

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Recurrent submicroscopic genomic copy number changes are the result of nonallelic homologous recombination (NAHR). Nonrecurrent aberrations, however, can result from different nonexclusive recombination-repair mechanisms. We previously described small microduplications at Xq28 containing MECP2 in four male patients with a severe neurological phenotype. Here, we report on the fine-mapping and breakpoint analysis of 16 unique microduplications. The size of the overlapping copy number changes varies between 0.3 and 2.3 Mb, and FISH analysis on three patients demonstrated a tandem orientation. Although eight of the 32 breakpoint regions coincide with low-copy repeats, none of the duplications are the result of NAHR. Bioinformatics analysis of the breakpoint regions demonstrated a 2.5-fold higher frequency of Alu interspersed repeats as compared with control regions, as well as a very high GC content (53%). Unexpectedly, we obtained the junction in only one patient by long-range PCR, which revealed nonhomologous end joining as the mechanism. Breakpoint analysis in two other patients by inverse PCR and subsequent array comparative genomic hybridization analysis demonstrated the presence of a second duplicated region more telomeric at Xq28, of which one copy was inserted in between the duplicated MECP2 regions. These data suggest a two-step mechanism in which part of Xq28 is first inserted near the MECP2 locus, followed by breakage-induced replication with strand invasion of the normal sister chromatid. Our results indicate that the mechanism by which copy number changes occur in regions with a complex genomic architecture can yield complex rearrangements.

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“…The X-chromosome has become an obvious focus for mapping and identifying genes for syndromal and nonspecific mental retardation. Published XLMR studies have been reviewed, and of 178 XLMRrelated genes, 120 genes are associated with mental retardation (Lubs et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

Effect of fetal exposure to bisphenol A on brain mediated by X-chromosome inactivation

Kumamoto

Oshio

2013

J. Toxicol. Sci.

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-Recent studies have reported that bisphenol A (BPA) influences brain development in fetal exposure to mice. The X-chromosome codes many neurodevelopment-related genes leading to abnormal development, such as mental retardation and intellectual deficiency. For females, most of expressions of X-linked genes are regulated by X-chromosome inactivation (XCI), which occurs during fetal period, and this mechanism is regulated by Xist and its antisense, Tsix. To clarify the possibility of X-mediated effect as a mechanism of neurodevelopmental disorders by BPA, pregnant ICR mice were orally administered 0.02 or 50 mg/kg of BPA on gestational days 6 and 15. Postnatally at days 2, 4 and weeks 3 and 7, mRNA expression of XCI-regulating factors (Xist and Tsix), X-linked neurodevelopment-related genes (Fmr1, Gdi1, Nlgn3, Pak3 and Ophn1), and sexual differentiation-related genes (ERα, ERβ and AR) were examined in cerebrums of female pups. Anogenital distance (AGD) and serum estradiol were also examined. In the 50 mg/kg exposed-group, reduced Xist, Fmr1, Gdi1, Nlgn3, and Pak3 and increased Tsix were observed simultaneously. Moderately reduced Xist, Gdi1, Nlgn3 and Pak3 were observed at 0.02 mg/kg BPA. ERα, ERβ and AR expression changes, shortened AGDs and reduced estradiol levels were observed in each exposure group. Fetal exposure to BPA changed expression of XCI-regulating factors and may alter the expression levels of X-linked neurodevelopment-related genes disrupting the XCI mechanism and function. This X-mediated effect is considered one of the mechanisms of various BPA-induced neurodevelopmental disorders.

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XLMR syndrome characterized by multiple respiratory infections, hypertelorism, severe CNS deterioration and early death localizes to distal Xq28

Cited by 61 publications

References 6 publications

De novo MECP2 duplication in two females with random X-inactivation and moderate mental retardation

De novo MECP2 duplication in two females with random X-inactivation and moderate mental retardation

Nonrecurrent MECP2 duplications mediated by genomic architecture-driven DNA breaks and break-induced replication repair

Effect of fetal exposure to bisphenol A on brain mediated by X-chromosome inactivation

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