Background Rubinstein–Taybi syndrome (RSTS) is a congenital neurodevelopmental disorder defined by postnatal growth deficiency, characteristic skeletal abnormalities and mental retardation and caused by mutations in the genes encoding for the transcriptional co-activators with intrinsic lysine acetyltransferase (KAT) activity CBP and p300. Previous studies have shown that neuronal histone acetylation is reduced in mouse models of RSTS.
Methods The authors identified different mutations at the CREBBP locus and generated lymphoblastoid cell lines derived from nine patients with RSTS carrying distinct CREBBP mutations that illustrate different grades of the clinical severity in the spectrum of the syndrome. They next assessed whether histone acetylation levels were altered in these cell lines.
Results The comparison of CREBBP-mutated RSTS cell lines with cell lines derived from patients with an unrelated mental retardation syndrome or healthy controls revealed significant deficits in histone acetylation, affecting primarily histone H2B and histone H2A. The most severe defects were observed in the lines carrying the whole deletion of the CREBBP gene and the truncating mutation, both leading to a haploinsufficiency state. Interestingly, this deficit was rescued by treatment with an inhibitor of histone deacetylases (HDACi).
Conclusions The authors' results extend to humans the seminal observations in RSTS mouse models and point to histone acetylation defects, mainly involving H2B and H2A, as relevant molecular markers of the disease.
- Rubinstein–Taybi syndrome
- CREBBP mutations
- histone acetylation
- cell biology
- memory disorders
- genetic screening/counselling
- clinical genetics
- congenital heart disease
- connective tissue disease
Statistics from Altmetric.com
AB and LL equally contributed to the work. JP L-A and CG equally contributed to the work.
Funding This study was supported by the Italy–Spain bilateral MIUR project (referred to as IT08143C4F in Italy and HI2007-0203 in Spain). Research at Larizza's lab is supported by a grant from ASM (Associazione Studio Malformazioni). Research at Barco's lab is supported by the grants from the Spanish Ministry of Science and Innovation BFU2008-00611, CSD2007-00023 and SAF2008-03194-E (part of the coordinated ERA-Net NEURON project Epitherapy) and a grant from Fundación Ramón Areces. JLA has a Juan de la Cierva contract given by the Spanish Ministry of Science and Innovation.
Competing interests None to declare.
Patient consent Obtained.
Ethics approval Ethics approval was provided by the University of Milan.
Provenance and peer review Not commissioned; externally peer reviewed.