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


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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    • "The genotype of patients without one of these mutations has also been investigated and some cases with gross rearrangements involving the MECP2 gene were found, usually large deletions. In boys, MECP2 duplication is the rare cause of a severe encephalopathy with recurrent infections, severe mental retardation, microcephaly and epilepsy (Ramocki et al., 2009; Van Esch et al., 2005). MECP2 duplication has also been described in a 0736-5748/© 2015 Elsevier Ltd. "
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    ABSTRACT: Rett syndrome is a neurodevelopmental disorder caused by mutations in the MECP2 gene. We investigated the genetic basis of disease in a female patient with a Rett-like clinical. Karyotype analysis revealed a pericentric inversion in the X chromosome -46,X,inv(X)(p22.1q28), with breakpoints in the cytobands where the MECP2 and CDKL5 genes are located. FISH analysis revealed that the MECP2 gene is not dislocated by the inversion. However, and in spite of a balanced pattern of X inactivation, this patient displayed hypomethylation and an overexpression of the MECP2 gene at the mRNA level in the lymphocytes (mean fold change: 2.55±0.38) in comparison to a group of control individuals; the expression of the CDKL5 gene was similar to that of controls (mean fold change: 0.98±0.10). No gains or losses were detected in the breakpoint regions encompassing known or suspected transcription regulatory elements. We propose that the de-regulation of MECP2 expression in this patient may be due to alterations in long-range genomic interactions caused by the inversion and hypothesize that this type of epigenetic de-regulation of the MECP2 may be present in other RTT-like patients. Copyright © 2015. Published by Elsevier Ltd.
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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.
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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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