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.

中文翻译：

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BRCC3 去泛素化酶的缺失导致血管生成异常，并与综合征性烟雾病有关。

烟雾病是一种脑血管病，其特征是颅内颈动脉末端部分进行性狭窄和异常脆弱的侧支血管（也称为烟雾病血管）代偿性发育，导致缺血性和出血性中风。烟雾病血管病可以是该疾病的唯一表现（烟雾病），也可以与多种疾病相关，包括神经纤维瘤病、唐氏综合征、TAAD（常染色体显性胸主动脉瘤）和头部肿瘤的放射治疗（烟雾病综合征）。它在日本的患病率是欧洲的十倍，日本估计有 6%-12% 的烟雾病是家族性的。这种情况的病理生理机制仍不清楚。这里，我们报告了三个不相关的家庭，这些家庭患有 X 连锁烟雾病综合征，其特征是烟雾病血管病、身材矮小和刻板的面部畸形。其他症状包括高促性腺激素性性腺功能减退症、高血压、扩张型心肌病、早发冠心病、早白头发和早期双侧获得性白内障。我们表明这种综合征性烟雾病是由 Xq28 缺失删除 MTCP1/MTCP1NB 和 BRCC3 引起的。我们还显示 brcc3 morphant 斑马鱼显示血管生成缺陷，这些缺陷被 brcc3 的内皮特异性表达所挽救。总之，这些数据强烈表明 BRCC3，一种去泛素化酶，是细胞 BRCA1 和 BRISC 复合物的一部分，