ABSTRACTBackground RubinsteineTaybi syndrome (RSTS) isa congenital neurodevelopmental disorder defined bypostnatal growth deficiency, characteristic skeletalabnormalities and mental retardation and caused bymutations in the genes encoding for the transcriptionalco-activators with intrinsic lysine acetyltransferase (KAT)activity CBP and p300. Previous studies have shown thatneuronal histone acetylation is reduced in mouse modelsof RSTS.Methods The authors identified different mutations atthe CREBBP locus and generated lymphoblastoid celllines derived from nine patients with RSTS carryingdistinct CREBBP mutations that illustrate different gradesof the clinical severity in the spectrum of the syndrome.They next assessed whether histone acetylation levelswere altered in these cell lines.Results The comparison of CREBBP-mutated RSTS celllines with cell lines derived from patients with anunrelated mental retardation syndrome or healthycontrols revealed significant deficits in histoneacetylation, affecting primarily histone H2B and histoneH2A. The most severe defects were observed in the linescarrying the whole deletion of the CREBBP gene and thetruncating mutation, both leading to a haploinsufficiencystate. Interestingly, this deficit was rescued by treatmentwith an inhibitor of histone deacetylases (HDACi).Conclusions The authors’ results extend to humans theseminal observations in RSTS mouse models and point tohistone acetylation defects, mainly involving H2B andH2A, as relevant molecular markers of the disease.
|Numero di pagine||9|
|Rivista||Journal of Medical Genetics|
|Stato di pubblicazione||Published - 2012|
All Science Journal Classification (ASJC) codes