Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Nature genetics, 2013-05, Vol.45 (5), p.556-562

Ort / Verlag

United States: Nature Publishing Group

Erscheinungsjahr

2013

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.