Loss of BRCC3 Deubiquitinating Enzyme Leads to Abnormal Angiogenesis and Is Associated with Syndromic Moyamoya

Miskinyte, S., Butler, M.G., Hervé, D., Sarret, C., Nicolino, M., Petralia, J.D., Bergametti, F., Arnould, M., Pham, V.N., Gore, A.V., Spengos, K., Gazal, S., Woimant, F., Steinberg, G.K., Weinstein, B.M., and Tournier-Lasserve, E.
American journal of human genetics   88(6): 718-28 (Journal)
Registered Authors
Butler, Matthew, Gore, Aniket, Pham, Van, Weinstein, Brant M.
MeSH Terms
  • Animals
  • Base Sequence
  • Blood Vessels/abnormalities*
  • Brain/blood supply
  • Chromosomes, Human, X/genetics*
  • Face/abnormalities
  • Female
  • Gene Deletion
  • Gene Knockdown Techniques
  • Genetic Diseases, X-Linked/genetics*
  • Humans
  • Male
  • Membrane Proteins/genetics*
  • Molecular Sequence Data
  • Moyamoya Disease/diagnosis
  • Moyamoya Disease/genetics*
  • Moyamoya Disease/pathology
  • Neovascularization, Physiologic/genetics*
  • Pedigree
  • Polymorphism, Single Nucleotide
  • Proto-Oncogene Proteins/genetics
  • Zebrafish/abnormalities
  • Zebrafish/genetics
21596366 Full text @ Am. J. Hum. Genet.
Moyamoya is a cerebrovascular angiopathy characterized by a progressive stenosis of the terminal part of the intracranial carotid arteries and the compensatory development of abnormal and fragile collateral vessels, also called moyamoya vessels, leading to ischemic and hemorrhagic stroke. Moyamoya angiopathy can either be the sole manifestation of the disease (moyamoya disease) or be associated with various conditions, including neurofibromatosis, Down syndrome, TAAD (autosomal-dominant thoracic aortic aneurysm), and radiotherapy of head tumors (moyamoya syndromes). Its prevalence is ten times higher in Japan than in Europe, and an estimated 6%-12% of moyamoya disease is familial in Japan. The pathophysiological mechanisms of this condition remain obscure. Here, we report on three unrelated families affected with an X-linked moyamoya syndrome characterized by the association of a moyamoya angiopathy, short stature, and a stereotyped facial dysmorphism. Other symptoms include an hypergonadotropic hypogonadism, hypertension, dilated cardiomyopathy, premature coronary heart disease, premature hair graying, and early bilateral acquired cataract. We show that this syndromic moyamoya is caused by Xq28 deletions removing MTCP1/MTCP1NB and BRCC3. We also show that brcc3 morphant zebrafish display angiogenesis defects that are rescued by endothelium-specific expression of brcc3. Altogether, these data strongly suggest that BRCC3, a deubiquitinating enzyme that is part of the cellular BRCA1 and BRISC complexes, is an important player in angiogenesis and that BRCC3 loss-of-function mutations are associated with moyamoya angiopathy.
Genes / Markers
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Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Engineered Foreign Genes
Errata and Notes