A partial <it>MECP2</it> duplication in a mildly affected adult male: a putative role for the 3' untranslated region in the <it>MECP2</it> duplication phenotype
<p>Abstract</p> <p>Background</p> <p>Duplications of the X-linked <it>MECP2</it> gene are associated with moderate to severe intellectual disability, epilepsy, and neuropsychiatric illness in males, while triplications are associated with a more severe pheno...
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2012-08-01T00:00:00Z.
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| Zusammenfassung: | <p>Abstract</p> <p>Background</p> <p>Duplications of the X-linked <it>MECP2</it> gene are associated with moderate to severe intellectual disability, epilepsy, and neuropsychiatric illness in males, while triplications are associated with a more severe phenotype. Most carrier females show complete skewing of X-inactivation in peripheral blood and an apparent susceptibility to specific personality traits or neuropsychiatric symptoms.</p> <p>Methods</p> <p>We describe the clinical phenotype of a pedigree segregating a duplication of <it>MECP2</it> found on clinical array comparative genomic hybridization. The position, size, and extent of the duplication were delineated in peripheral blood samples from affected individuals using multiplex ligation-dependent probe amplification and fluorescence <it>in situ</it> hybridization, as well as targeted high-resolution oligonucleotide microarray analysis and long-range PCR. The molecular consequences of the rearrangement were studied in lymphoblast cell lines using quantitative real-time PCR, reverse transcriptase PCR, and western blot analysis.</p> <p>Results</p> <p>We observed a partial <it>MECP2</it> duplication in an adult male with epilepsy and mild neurocognitive impairment who was able to function independently; this phenotype has not previously been reported among males harboring gains in <it>MECP2</it> copy number. The same duplication was inherited by this individual's daughter who was also affected with neurocognitive impairment and epilepsy and carried an additional copy-number variant. The duplicated segment involved all four exons of <it>MECP2</it>, but excluded almost the entire 3' untranslated region (UTR)<it>,</it> and the genomic rearrangement resulted in a <it>MECP2</it>-<it>TEX28</it> fusion gene mRNA transcript. Increased expression of <it>MECP2</it> and the resulting fusion gene were both confirmed; however, western blot analysis of lysates from lymphoblast cells demonstrated increased MeCP2 protein without evidence of a stable fusion gene protein product.</p> <p>Conclusion</p> <p>The observations of a mildly affected adult male with a <it>MECP2</it> duplication and paternal transmission of this duplication are unique among reported cases with a duplication of <it>MECP2</it>. The clinical and molecular findings imply a minimal critical region for the full neurocognitive expression of the <it>MECP2</it> duplication syndrome, and suggest a role for the 3' UTR in mitigating the severity of the disease phenotype.</p> |
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| Beschreibung: | 10.1186/1471-2350-13-71 1471-2350 |