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Mutations in STAMBP, encoding a deubiquitinating enzyme, cause microcephaly–capillary malformation syndrome

2013; Nature Portfolio; Volume: 45; Issue: 5 Linguagem: Inglês

10.1038/ng.2602

1546-1718

Laura M. McDonell, Ghayda Mirzaa, Diana Alcantara, Jeremy Schwartzentruber, Melissa T. Carter, Leo J. Lee, Carol L. Clericuzio, John M. Graham, Deborah J. Morris‐Rosendahl, Tilman Polster, Gyula Acsádi, Sharron Townshend, Simon Williams, Anne Halbert, Bertrand Isidor, Albert David, Christopher D. Smyser, Alex R. Paciorkowski, Marcia Willing, John Woulfe, Soma Das, Chandree L. Beaulieu, Janet Marcadier, Michael T. Geraghty, Brendan J. Frey, Jacek Majewski, Dennis E. Bulman, William B. Dobyns, Mark O’Driscoll, Kym M. Boycott,

Genetic and Kidney Cyst Diseases

Kym Boycott, Mark O'Driscoll and colleagues report identification of mutations in STAMBP, a gene encoding the deubiquitinating isopeptidase STAMBP, in individuals with microcephaly–capillary malformation syndrome. 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.