Am J Hum Genet. 2011 Jun 10;88(6):718-728. doi: 10.1016/j.ajhg.2011.04.017. Epub 2011 May 19.

Loss of BRCC3 deubiquitinating enzyme leads to abnormal angiogenesis and is associated with syndromic moyamoya.

Miskinyte S¹, Butler MG², Hervé D³, Sarret C⁴, Nicolino M⁵, Petralia JD⁶, Bergametti F¹, Arnould M¹, Pham VN², Gore AV², Spengos K⁷, Gazal S⁸, Woimant F³, Steinberg GK⁶, Weinstein BM², Tournier-Lasserve E⁹.

Author information

1: INSERM UMR-S-740; Université Paris, 7 Denis Diderot, 10 Avenue de Verdun, 75010 Paris, France.
2: Program in Genomics of Differentiation, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892.
3: Assistance Publique des Hôpitaux de Paris, Groupe Hospitalier Lariboisière-Saint-Louis, Service de Neurologie, Centre de Référence des Maladies Vasculaires Rares du Cerveau et de l'Oeil, F-75010 Paris, France.
4: Hospices Civils de Lyon, Groupe Hospitalier Est, Hôpital Femme-Mère-Enfant, Service de Neurologie Pédiatrique, 69677 Bron, France.
5: Division of Pediatric Endocrinology, Lyon University Pediatric Hospital, INSERM U.870, Centre d'Investigation Clinique 201, Université Claude Bernard Lyon 1, Hospices Civils de Lyon, Lyon, France.
6: Department of Neurosurgery, Stanford Stroke Center and Stanford Institute for Neuro-Innovation and Translational Neurosciences, Stanford University School of Medicine, Stanford, California, USA.
7: First Department of Neurology, Eginition Hospital, National and Kapodestrian University of Athens, School of Medicine, 11528 Athens, Greece.
8: Assistance Publique des Hôpitaux de Paris, Plateforme de Génomique Constitutionnelle du Groupe Hospitalo Universitaire Nord, Hôpital Bichat, F-75010 Paris, France.
9: INSERM UMR-S-740; Université Paris, 7 Denis Diderot, 10 Avenue de Verdun, 75010 Paris, France; Assistance Publique des Hôpitaux de Paris, Groupe Hospitalier Lariboisière-Saint-Louis, Laboratoire de Génétique, Centre de Référence des Maladies Vasculaires Rares du Cerveau et de l'Oeil, F-75010 Paris, France. Electronic address: tournier-lasserve@univ-paris-diderot.fr.

Abstract

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.