2. Academic Validation
  3. Mutations in STAMBP, encoding a deubiquitinating enzyme, cause microcephaly-capillary malformation syndrome

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

Affiliation

  • 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.

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