title: Mutations in STAMBP, encoding a deubiquitinating enzyme, cause microcephaly-capillary malformation syndrome.
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.
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Laura M
authors.initials: LM
authors.lastname: McDonell
authors.forename: Ghayda M
authors.initials: GM
authors.lastname: Mirzaa
authors.forename: Diana
authors.initials: D
authors.lastname: Alcantara
authors.forename: Jeremy
authors.initials: J
authors.lastname: Schwartzentruber
authors.forename: Melissa T
authors.initials: MT
authors.lastname: Carter
authors.forename: Leo J
authors.initials: LJ
authors.lastname: Lee
authors.forename: Carol L
authors.initials: CL
authors.lastname: Clericuzio
authors.forename: John M
authors.initials: JM
authors.lastname: Graham
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Morris-Rosendahl
authors.forename: Tilman
authors.initials: T
authors.lastname: Polster
authors.forename: Gyula
authors.initials: G
authors.lastname: Acsadi
authors.forename: Sharron
authors.initials: S
authors.lastname: Townshend
authors.forename: Simon
authors.initials: S
authors.lastname: Williams
authors.forename: Anne
authors.initials: A
authors.lastname: Halbert
authors.forename: Bertrand
authors.initials: B
authors.lastname: Isidor
authors.forename: Albert
authors.initials: A
authors.lastname: David
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Smyser
authors.forename: Alex R
authors.initials: AR
authors.lastname: Paciorkowski
authors.forename: Marcia
authors.initials: M
authors.lastname: Willing
authors.forename: John
authors.initials: J
authors.lastname: Woulfe
authors.forename: Soma
authors.initials: S
authors.lastname: Das
authors.forename: Chandree L
authors.initials: CL
authors.lastname: Beaulieu
authors.forename: Janet
authors.initials: J
authors.lastname: Marcadier
authors.forename: Michael T
authors.initials: MT
authors.lastname: Geraghty
authors.forename: Brendan J
authors.initials: BJ
authors.lastname: Frey
authors.forename: Jacek
authors.initials: J
authors.lastname: Majewski
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Bulman
authors.forename: William B
authors.initials: WB
authors.lastname: Dobyns
authors.forename: Mark
authors.initials: M
authors.lastname: O'Driscoll
authors.forename: Kym M
authors.initials: KM
authors.lastname: Boycott
mesh_terms: D002196:Capillaries / Q000473:pathology*; D016022:Case-Control Studies; D002675:Child, Preschool; D015331:Cohort Studies; D002658:Developmental Disabilities / Q000235:genetics* / Q000473:pathology; D056827:Endosomal Sorting Complexes Required for Transport / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D004827:Epilepsy / Q000235:genetics* / Q000473:pathology; D059472:Exome / Q000235:genetics; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D005808:Genes, Recessive; D015894:Genome, Human; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D008831:Microcephaly / Q000235:genetics* / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics; D012871:Skin Diseases / Q000235:genetics* / Q000473:pathology; D013577:Syndrome; D043222:Ubiquitin Thiolesterase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
chemical_list: D056827:Endosomal Sorting Complexes Required for Transport; D034741:RNA, Small Interfering; C486696:STAMBP protein, human; D043222:Ubiquitin Thiolesterase
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