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

Laura M. McDonell, Ghayda M. Mirzaa, Diana Alcantara, Jeremy Schwartzentruber, Melissa T. Carter, Leo J. Lee, Carol L. Clericuzio, John M. Graham, Deborah J. Morris-Rosendahl, Tilman Polster, Gyula Acsadi, Sharron Townshend, Simon Williams, Anne Halbert, Bertrand Isidor, Albert David, Christopher D. Smyser, Alex R. Paciorkowski, Marcia Willing, John WoulfeSoma 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

Research output: Contribution to journalArticle

52 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)556-562
Number of pages7
JournalNature Genetics
Volume45
Issue number5
DOIs
StatePublished - May 2013

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    McDonell, L. M., Mirzaa, G. M., Alcantara, D., Schwartzentruber, J., Carter, M. T., Lee, L. J., Clericuzio, C. L., Graham, J. M., Morris-Rosendahl, D. J., Polster, T., Acsadi, G., Townshend, S., Williams, S., Halbert, A., Isidor, B., David, A., Smyser, C. D., Paciorkowski, A. R., Willing, M., ... Boycott, K. M. (2013). Mutations in STAMBP, encoding a deubiquitinating enzyme, cause microcephaly-capillary malformation syndrome. Nature Genetics, 45(5), 556-562. https://doi.org/10.1038/ng.2602