Mutation in EZR inhibits the Ras/MAP pathway and causes autosomal recessive intellectual disability. R. Abou Jamra1, L. B. Riecken2, H. Tawamie1, K. Geissler2, A. Schulz2, R. Buchert1, S. Uebe1, M. M. Nöthen3,4, J. Schumacher3, A. Ismael5, A. Ekici1, H. Sticht6, A. Reis1, H. Morrison2 1) Institute of Human Genetics, Friedrich-Alexander-Universitat Erlangen-Nurnberg, Erlangen, Bavaria, Germany; 2) Leibniz Institute for Age Research, Fritz Lipmann Institute, Jena, Thuringia, Germany; 3) Institute of Human Genetics, University of Bonn, Bonn, NRW, Germany; 4) Life and Brain Center, University of Bonn, Bonn, NRW, Germany; 5) Praxis of Pediatrics, Jesser El Sheghour, Idlib, Syria; 6) Institute of Biochemistry, Friedrich-Alexander-Universitat Erlangen-Nurnberg, Erlangen, Bavaria, Germany.

   We examined a large consanguineous family with intellectual disability. The family has two sons with severe non-specific intellectual disability and early epilepsy. Brain CT scan showed enlargement and deformation of the ventricles, periventricular leukomalacia, cerebral atrophy, dysplasia of corpus callosum, and reduction in the white matter in both hemispheres. We undertook autozygosity mapping and identified three candidate loci on chromosomes 6, (8.1 Mb), 18 (2.7 Mb), and 22 (7.8 Mb). We then enriched the exome of the index patient with Agilent SureSelect Kit 50 Mb and sequenced it on SOLiD 5500XL. We identified two novel homozygous variants in EZR (p.A129T) and MAP3K4 (p.M577V). The mutated alanine in EZR is highly conserved. In silico analysis using three programs predicted a pathogenic effect of the identified variant. Comprehensive molecular modelling on protein level showed that the mutation in EZR buries the hydrophilic threonine in the hydrophobic core and thus destabilizes the protein structure, probably leading to a strong effect on the protein function. EZR encodes ezrin, a member of the ERM (ezrin, radixin and moesin) protein family, which shares the FERM (four point one ERM homology) domain. Ezrin is necessary for a number of cellular processes, such as cell adhesion, motility, morphogenesis and cell signaling. The identified mutation is located in the FERM domain, which has binding sites for many membrane and signaling molecules. Because we recently showed that ezrin is required for the activity control of the small GTPase Ras we measured the effect of the ezrin mutant specifically on Ras. We transfected NIH3T3 cells with the wild type or mutated EZR. NIH3T3 cells expressing mutant ezrin blocked growth factor induced Ras activity. As a consequence of the inhibition of Ras we observed a decrease in proliferation. These in vitro cellular assays show that this mutation has a drastic effect on the ezrin protein and expression of which leads to an abnormal cellular phenotype. We suppose that this effect exists also in neurons and causes the severe phenotype of the examined family. Further experiments are ongoing. Taken together, we were able to identify EZR as a novel gene causing severe autosomal recessive non-specific intellectual disability. The loss of function of the ezrin mutant with the observed defects in Ras signaling is in line with other phenotypes of neurodevelopmental disorders and defects in Ras/MAP pathway.

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