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

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posted on 2023-06-08, 14:39 authored by Laura M McDonell, Ghayda M Mirzaa, Diana AlcantaraDiana 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 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'DriscollMark O'Driscoll, Kym M Boycott
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.

History

Publication status

  • Published

Journal

Nature genetics

ISSN

1546-1718

Publisher

Nature Publishing Group

Issue

5

Volume

45

Page range

556-562

Department affiliated with

  • Sussex Centre for Genome Damage Stability Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2013-04-03

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