 Hi, I'm Rami Abu Jamrah. I'm a medical doctor and a human geneticist. I work at the Institute of Human Genetics in Erlangen. I met a family that has two children with intellectual disability and they asked me if I can know the reason that would be of great advantage for them. It looked like or to some a recessive. I made mapping and sequencing and I identified a very interesting candidate mutation in his brain. To functionally characterize it, I thought that I must find somebody who knows that, who can do it and who is interested. I was very lucky to find a group of Helen Morrison and Jena. Helen is working with this gene and she is an expert so I think it's the time to give up to Helen. Hello, my name is Helen Morrison. I'm a biologist working at the Leibniz Institute for Age Research in Jena. Our lab studies escharine function in the nervous system so for this particular study I'd like to hand over to Lars who is the first author and he can very well explain the study. Hello, I'm Lars Witten. I'm a PhD student at the Morrison Lab and first author of our study published in Human Mutation. In the study we identified an inhibition of RAS activation due to homozygous escharine variant in patients with profound intellectual disability. We examined the family with one healthy daughter and two affected sons. The boys showed severe intellectual disability, a partial malformation of the brain and a developmental delay that was obvious as early as three months of age. Following exome sequencing, filtering and in silico prediction of pathogenicity, we identified a single variant located in EZR, the gene coding for the protein escharine. Escharine is classically known for linking membrane proteins to the actin cytoskeleton, thereby organizing cell polarity and architecture. Membrane binding is mediated by the firm domain, which also contains the identified variant. However, using fluorescently labeled proteins, we did not detect any differences in membrane targeting or subcellular localization. In addition to Escharine's linker function, we recently identified also a role in growth factor signaling, where Escharine assists activation of the small GDPS RAS. RAS in turn is essential for many cellular processes, including proliferation and neuronal differentiation. The identified escharine variant is located within the firm's subdomain F2. Modeling this variant into Escharine's crystal structure suggested a disturbance of its local conformation. Modeling the variant into the related structure of CRAT1 further suggested that this variant may disturb an important binding surface used for small GDPS binding. We had previously reported that Escharine can directly bind RAS via its firm domain. Therefore, we investigated whether this binding of RAS is disturbed by the identified variant. Indeed, we found that RAS binding was strongly impaired, both in complexes isolated from cellular lysates, as well as in direct binding assays using purified recombinant proteins. As a downstream consequence, the variant also inhibited growth factor-induced RAS activation and cellular proliferation. In summary, our data indicates that the identified Escharine variant inhibits proper formation of a previously identified RAS activation complex. The variant precludes RAS from this complex, thus prevents its activation and inhibits RAS-dependent cellular processes. We suggest that this Escharine variant constitutes a novel type of developmental RAS pathway disturbance that is characterized by reduced RAS activity. Classically, developmental RAS pathway disturbances are characterized by a hyperactivation of the pathway due to dominantly inherited variants. In contrast, our data indicates that the identified Escharine variant is the first recessively inherited variant that leads to reduced RAS pathway activity and therefore may represent a novel counterpart to the classic RASopathies. We hope you enjoyed our video abstract. For further information, please refer to our publication at Human Mutation. And for further questions, please do not hesitate to contact us. Thank you very much.