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

  • Nat Genet. 2013 May;45(5):556-62. doi: 10.1038/ng.2602.
Laura M McDonell  1 ,  Ghayda M Mirzaa ,  Diana Alcantara ,  Jeremy Schwartzentruber ,  Melissa T Carter ,  Leo J Lee ,  Carol L Clericuzio ,  John M Graham Jr ,  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 Woulfe ,  Soma Das ,  Chandree L Beaulieu ,  Janet Marcadier ,  FORGE Canada Consortium ,  Michael T Geraghty ,  Brendan J Frey ,  Jacek Majewski ,  Dennis E Bulman ,  William B Dobyns ,  Mark O'Driscoll ,  Kym M Boycott
Affiliations
  • 1. Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
PMID: 23542699 DOI: 10.1038/ng.2602
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.