Microcephaly–capillary malformation (MIC-CAP) syndrome is characterized by severe microcephaly with progressive cortical atrophy, intractable epilepsy, profound developmental delay and multiple small capillary malformations on the skin. We used whole-exome sequencing of five patients with MIC-CAP syndrome and identified recessive mutations in STAMBP, a gene encoding the deubiquitinating (DUB) isopeptidase STAMBP (STAM-binding protein, also known as AMSH, associated molecule with the SH3 domain of STAM) that has a key role in cell surface receptor–mediated endocytosis and sorting. Patient cell lines showed reduced STAMBP expression associated with accumulation of ubiquitin-conjugated protein aggregates, elevated apoptosis and insensitive activation of the RAS-MAPK and PI3K-AKT-mTOR pathways. The latter cellular phenotype is notable considering the established connection between these pathways and their association with vascular and capillary malformations. Furthermore, our findings of a congenital human disorder caused by a defective DUB protein that functions in endocytosis implicates ubiquitin-conjugate aggregation and elevated apoptosis as factors potentially influencing the progressive neuronal loss underlying MIC-CAP syndrome.
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NCBI Reference Sequence
The authors would like to thank the study patients and their families, without whose participation this work would not be possible. This work was funded by the Government of Canada through Genome Canada, the Canadian Institutes of Health Research (CIHR) and the Ontario Genomics Institute (OGI-049) (to K.M.B.). Additional funding was provided by Genome Quebec and Genome British Columbia (to K.M.B.), the US National Institutes of Health under National Institute of Neurological Disorders and Stroke (NINDS) grant NS058721 (to W.B.D.), as well as National Institute of Child Health and Human Development (NICHD) grant HD36657 and National Institute of General Medicine Sciences (NIGMS) grant 5-T32-GM08243 (to J.M.G.) and the Leukaemia Lymphoma Research (UK), Medical Research Council (UK) and Cancer Research UK (CR-UK) (to M.O.). The authors acknowledge the contribution of the high-throughput sequencing platform of the McGill University and Génome Québec Innovation Centre, Montréal, Canada, as well as M. Moellers, (Pediatric Radiology, Evangelisches Krankenhaus Bielefeld). This work was selected for study by the FORGE Canada Steering Committee, consisting of K. Boycott (University of Ottawa), J. Friedman (University of British Columbia), J. Michaud (University of Montreal), F. Bernier (University of Calgary), M. Brudno (University of Toronto), B. Fernandez (Memorial University), B. Knoppers (McGill University), M. Samuels (University of Montreal) and S. Scherer (University of Toronto). L.M.M. is supported by a Frederick Banting Graduate Scholarship from CIHR. M.O. is a CR-UK Senior Cancer Research Fellow. K.M.B. is supported by a Clinical Investigatorship Award from the CIHR Institute of Genetics.
Supplementary Figures 1–6 and Supplementary Tables 1–3