Duplication of the MECP2 Region Is a Frequent Cause of Severe Mental Retardation and Progressive Neurological Symptoms in Males

Centre for Human Genetics, University Hospital Gasthuisberg, Leuven, Belgium.
The American Journal of Human Genetics (Impact Factor: 10.93). 10/2005; 77(3):442-53. DOI: 10.1086/444549
Source: PubMed

ABSTRACT Loss-of-function mutations of the MECP2 gene at Xq28 are associated with Rett syndrome in females and with syndromic and nonsyndromic forms of mental retardation (MR) in males. By array comparative genomic hybridization (array-CGH), we identified a small duplication at Xq28 in a large family with a severe form of MR associated with progressive spasticity. Screening by real-time quantitation of 17 additional patients with MR who have similar phenotypes revealed three more duplications. The duplications in the four patients vary in size from 0.4 to 0.8 Mb and harbor several genes, which, for each duplication, include the MR-related L1CAM and MECP2 genes. The proximal breakpoints are located within a 250-kb region centromeric of L1CAM, whereas the distal breakpoints are located in a 300-kb interval telomeric of MECP2. The precise size and location of each duplication is different in the four patients. The duplications segregate with the disease in the families, and asymptomatic carrier females show complete skewing of X inactivation. Comparison of the clinical features in these patients and in a previously reported patient enables refinement of the genotype-phenotype correlation and strongly suggests that increased dosage of MECP2 results in the MR phenotype. Our findings demonstrate that, in humans, not only impaired or abolished gene function but also increased MeCP2 dosage causes a distinct phenotype. Moreover, duplication of the MECP2 region occurs frequently in male patients with a severe form of MR, which justifies quantitative screening of MECP2 in this group of patients.

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Available from: Jaakko Ignatius, Sep 28, 2015
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    • "In some cases, deletions and duplications of the same dosagesusceptible gene give rise to different clinical conditions, as previously shown, for example, for SOX9, MECP2, or PMP22 (Benko et al. 2009; Kurth et al. 2009; Meins et al. 2005; Van Esch et al. 2005; Patel et al. 1992; Valentijn et al. 1995; Chance et al. 1993). Alternatively, CNVs can also cause position effects and disturb gene expression by changing the number or location of regulatory elements or by altering the entire regulatory landscape of a target gene or gene cluster (Klopocki and Mundlos 2011). "
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    ABSTRACT: Loss-of-function mutations of the KAL1 gene are a known cause of Kallmann syndrome, a disorder characterized by the coexistence of hypogonadotropic hypogonadism and anosmia/hiposmia. On the other hand, neither complete nor partial duplications of KAL1 have been reported in the literature; thus, clinical symptoms associated with such alterations remain unknown. Ectrodactyly is a clinically and genetically heterogeneous abnormality presenting with hypoplasia of the central rays of the extremity, which, in around 68 % of cases, has unknown underlying molecular defect. In this paper, we report on a sporadic male patient manifesting hyperosmia and ectrodactyly accompanied by additional symptoms involving mild intellectual disability, unilateral hearing loss, genital anomalies, stocky build, and facial dysmorphism. Using a combination of high-resolution array comparative genomic hybridization (array CGH) and breakpoint analysis, we detected a hemizygous tandem duplication of 110,967 bp on Xp22.31, encompassing the promoter region and the first two exons of KAL1. In order to confirm pathogenicity of the duplication, we tested the level of KAL1 transcript in blood lymphocytes, showing 79 times higher expression in the proband compared to controls. We, therefore, hypothesize that olfactory hypersensitivity in our proband directly results from KAL1 overproduction. Additionally, a literature review allowed us to conclude that KAL1 protein at high levels may interfere with FGFR1 signaling activity, most probably indirectly giving rise to ectrodactyly, intellectual disability, and genital anomalies. Noteworthy, those symptoms overlap with Hartsfield syndrome caused by FGFR1 loss-of-function mutations. To conclude, our paper highlights the role of KAL1 in embryogenesis and provides data on the contribution of KAL1 overexpression to human pathology.
    Journal of applied genetics 10/2014; 56(2). DOI:10.1007/s13353-014-0252-7 · 1.48 Impact Factor
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    • "We previously demonstrated highly stable MECP2 mRNA levels in male and female controls (Van Esch et al. 2005). qPCR expression analysis in RNA from EBV-PBLs from patient 1 demonstrated increased mRNA levels for MECP2 and GDI1, both present within the duplication, when compared to EBV-PBLs from two female controls (mean 3.5-and 3.8-fold, respectively) (online supplementary Fig. 5A). "
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    ABSTRACT: Xq28 microduplications of MECP2 are a prominent cause of a severe syndromic form of intellectual disability (ID) in males. Females are usually unaffected through near to complete X-inactivation of the aberrant X chromosome (skewing). In rare cases, affected females have been described due to random X-inactivation. Here, we report on two female patients carrying de novo MECP2 microduplications on their fully active X chromosomes. Both patients present with ID and additional clinical features. Mono-allelic expression confirmed complete skewing of X-inactivation. Consequently, significantly enhanced MECP2 mRNA levels were observed. We hypothesize that the cause for the complete skewing is due to a more harmful mutation on the other X chromosome, thereby forcing the MECP2 duplication to become active. However, we could not unequivocally identify such a second mutation by array-CGH or exome sequencing. Our data underline that, like in males, increased MECP2 dosage in females can contribute to ID too, which should be taken into account in diagnostics.
    Human Genetics 07/2014; 133(11). DOI:10.1007/s00439-014-1469-6 · 4.82 Impact Factor
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    • "In particular, we introduce the novel idea that high expression of MECP2 in mitotic cells leads to antiproliferative and apoptotic effects. Several cases of increased MECP2 copy number have been reported in male patients with progressive neurodevelopmental delay phenotype (Friez et al., 2006; Lugtenberg et al., 2006; Meins et al., 2005; Van Esch et al., 2005). Interestingly, a male patient with triplication of the MECP2 locus was described to have an even worse early-onset neurological phenotype at 3 months of age (del Gaudio et al., 2006), suggesting that the severity of an MECP2 overexpression phenotype is proportional to the copy number increase. "
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    ABSTRACT: Epigenetic mechanisms are fundamental for shaping the activity of the central nervous system (CNS). Methyl-CpG binding protein 2 (MECP2) acts as a bridge between methylated DNA and transcriptional effectors responsible for differentiation programs in neurons. The importance of MECP2 dosage in CNS is evident in Rett Syndrome and MECP2 duplication syndrome, which are neurodevelopmental diseases caused by loss-of-function mutations or duplication of the MECP2 gene, respectively. Although many studies have been performed on Rett syndrome models, little is known about the effects of an increase in MECP2 dosage. Herein, we demonstrate that MECP2 overexpression affects neural tube formation, leading to a decrease in neuroblast proliferation in the neural tube ventricular zone. Furthermore, an increase in MECP2 dose provokes premature differentiation of neural precursors accompanied by greater cell death, resulting in loss of neuronal populations. Overall, our data indicate that correct MECP2 expression levels are required for proper nervous system development.
    Neurobiology of Disease 07/2014; 67. DOI:10.1016/j.nbd.2014.03.009 · 5.08 Impact Factor
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