Variegated silencing through epigenetic modifications of a large Xq region in a case of balanced X;2 translocation with Incontinentia Pigmenti-like Phenotype

Rita Genesio, Daniela Melis, Sole Gatto, Antonella Izzo, Valentina Ronga, Gerarda Cappuccio, Ambra Lanzo, Generoso Andria, Maurizio D'Esposito, Maria R. Matarazzo, Anna Conti, Lucio Nitsch

Research output: Contribution to journalArticle

Abstract

Molecular mechanisms underlying aberrant phenotypes in balanced X;autosome translocations are scarcely understood. We report the case of a de novo reciprocal balanced translocation X;2(q23;q33) presenting phenotypic alterations highly suggestive of Incontinentia Pigmenti (IP) syndrome, a genodermatosis with abnormal skin pigmentation and neurological failure, segregating as X-linked dominant disorder. Through molecular studies, we demonstrated that the altered phenotype could not be ascribed to chromosome microdeletions or to XIST-mediated inactivation of Xq24-qter. Interestingly, we found that the Xq24-qter region, which translocated downstream of the heterochromatic band 2q34, undergoes epigenetic silencing mediated by DNA methylation and histone alterations. Among the downregulated genes, we found the inhibitor of kappa light polypeptide gene enhancer in B cells, kinase gamma (IKBKG/NEMO), the causative gene of IP. We hypothesize that a mosaic functional nullisomy of the translocated genes, through a Position Effect Variegationlike heterochromatization, might be responsible for the proband's phenotypic anomalies. Partial silencing of IKBKG may be responsible for the skin anomalies observed, thereby mimicking the IP pathological condition. In addition to its clinical relevance, this paper addresses fundamental issues related to the chromatin status and nuclear localization of a human euchromatic region translocated proximally to heterochromatin. In conclusion, the study provides new insight into long-range gene silencing mechanisms and their direct impact in human disease.

Original languageEnglish
Pages (from-to)1242-1247
Number of pages6
JournalEpigenetics
Volume6
Issue number10
DOIs
Publication statusPublished - Oct 2011

Keywords

  • Autosome translocation
  • Epigenetic silencing
  • IKBKG
  • Incontinentia pigmenti
  • PEV-like heterochromatization
  • X

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

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  • Cite this

    Genesio, R., Melis, D., Gatto, S., Izzo, A., Ronga, V., Cappuccio, G., Lanzo, A., Andria, G., D'Esposito, M., Matarazzo, M. R., Conti, A., & Nitsch, L. (2011). Variegated silencing through epigenetic modifications of a large Xq region in a case of balanced X;2 translocation with Incontinentia Pigmenti-like Phenotype. Epigenetics, 6(10), 1242-1247. https://doi.org/10.4161/epi.6.10.17698