title: Variegated silencing through epigenetic modifications of a large Xq region in a case of balanced X;2 translocation with Incontinentia Pigmenti-like phenotype.
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 Variegation-like 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.
authors.affiliation: Cellular and Molecular Biology and Pathology Department; University of Naples Federico II, Naples, Italy.
authors.forename: Rita
authors.initials: R
authors.lastname: Genesio
authors.forename: Daniela
authors.initials: D
authors.lastname: Melis
authors.forename: Sole
authors.initials: S
authors.lastname: Gatto
authors.forename: Antonella
authors.initials: A
authors.lastname: Izzo
authors.forename: Valentina
authors.initials: V
authors.lastname: Ronga
authors.forename: Gerarda
authors.initials: G
authors.lastname: Cappuccio
authors.forename: Ambra
authors.initials: A
authors.lastname: Lanzo
authors.forename: Generoso
authors.initials: G
authors.lastname: Andria
authors.forename: Maurizio
authors.initials: M
authors.lastname: D'Esposito
authors.forename: Maria R
authors.initials: MR
authors.lastname: Matarazzo
authors.forename: Anna
authors.initials: A
authors.lastname: Conti
authors.forename: Lucio
authors.initials: L
authors.lastname: Nitsch
mesh_terms: D041321:Chromosomes, Human, X; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D020868:Gene Silencing; D006657:Histones / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics; D007184:Incontinentia Pigmenti / Q000235:genetics*; D010641:Phenotype; D014178:Translocation, Genetic
chemical_list: D006657:Histones; C491731:IKBKG protein, human; D051550:I-kappa B Kinase