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Discovery of a new gene involved in intellectual disability

In the case of mutation of BRPF1, the modifiers hEAF6 and ING5 are not recruited and the complex is then unable to acetylate histone H3.

Mutations in Histone Acetylase Modifier BRPF1 Cause an Autosomal-Dominant Form of Intellectual Disability with Associated Ptosis.

Mattioli F(1), Schaefer E(2), Magee A(3), Mark P(4), Mancini GM(5), Dieterich K(6), Von Allmen G(7), Alders M(8), Coutton C(9), van Slegtenhorst M(5), Vieville G(9), Engelen M(8), Cobben JM(8), Juusola J(10), Pujol A(11), Mandel JL(12), Piton A(13).

Am J Hum Genet Jan. 5, 2017

Dec. 7, 2016

Francesca Mattioli and Amélie Piton of Jean-Louis Mandel’s team have just highlighted a new gene involved in intellectual disability. Their results are published on December 7, 2016 in The American Journal of Human Genetics.

BRPF1, a new DI gene
Intellectual disability (ID) encompasses a set of neurodevelopmental disorders characterized by high genetic heterogeneity, with several hundred genes involved. An analysis carried out in a family comprising six individuals with mild ID, revealed a mutation in the BRPF1 gene, involving for the first time this gene in this disease. Six other mutations affecting the same gene (point mutations and total gene deletions) were then identified in individuals with similar clinical symptoms. BRPF1 is located near SETD5, another gene involved in ID, on chromosome 3p25. Researchers have demonstrated that these two genes participate in the clinical manifestations of the 3p25 microdeletion syndrome: in the case of mutation on one of these genes, ID is mild; but if both are mutated, the symptoms are more severe.


The third member of a complex involved in histone acetylation
The regulation of gene expression involves many processes, including changes in the structure of chromatin via modifications of histone proteins which are responsible for the DNA condensation. The BRPF1 gene encodes a protein forming part of a proteic complex whose function is to add an acetyl group to histone H3. This histone acetylase activity is carried out by two proteins of this complex whose genes, KAT6A and KAT6B, are also known to be involved in ID forms. It is thus the third gene encoding a protein of the same complex involved in a form of ID. At the molecular level, the researchers were able to show that the mutation identified in the BRPF1 gene affected the localization of the protein. Although its interaction with KAT6A and KAT6B was unaffected, the recruitment of complex modifiers was, then inhibiting the acetyltransferase activity of the complex.


BRPF1 therefore completes the long list of genes involved in intellectual impairment that play a role in the control of gene expression through the regulation of changes in the structure of chromatin.


This study was funded by the Fondation Maladies Rares, the Collège de France and the Fondation Jérôme Lejeune.

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