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

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.

Neurosurgical Advances in the Treatment of Moyamoya Disease

“…7 Recently Xq28 deletions removing MTCP1/ MTCP1NB and BRCC3 have been shown to cause a type of X-linked familial moyamoya syndrome. 8 A number of growth factors are thought to be associated with MMD. Because of the extensive collateral formation defining MMD, research has focused on vascular and angiogenic factors.…”

Haemophilia A and cardiovascular morbidity in a female SHAM syndrome carrier due to skewed X chromosome inactivation

“…1), none of these genes is a plausible candidate for the phenotypic features observed in the SHAM syndrome patient or a symptomatic female carrier. The role for BRCC3, a ubiquitin ligase involved in DNA damage response complexes, in the development of vessels was elegantly shown in the original report by Miskinyte et al using a zebrafish model (with endothelium-specific expression of brcc3 rescuing the angiogenesis defects) (Miskinyte et al, 2011). In another report, BRCC3 was demonstrated to be a component of a deubiquitinating complex that was implicated in protection of cardiomyocytes from cellular stress-related apoptosis (Cilenti et al, 2011).…”

“…Further studies into BRCC3 role are warranted at both clinical and mechanistic level, in particular it is not known whether the role of BRCC3 in moyamoya is related to its role in DNA damage signalling. Of note is the relatively frequent occurrence of secondary moyamoya following cranial irradiation that is likely dependent on DNA damage or hypoxia signalling that could be similar to those associated with BRCC3 loss (Miskinyte et al, 2011;Sigdel et al, 2013).…”

“…The genetic analysis of the family of our SHAM patient provided evidence of carrier state (identical heterozygous deletion e as shown in Fig. 1) in proband's mother and sister (Janczar et al, 2014(Janczar et al, , 2015Miskinyte et al, 2011). Von Willebrand disease, which might affect factor VIII level, was excluded in all presented family members using measurement of plasma level of von Willebrand factor and its activity.…”

Advances in Stroke

“…[13][14][15] Novel molecular genetics tools also recently led to the identification of several genes involved in other stroke conditions, such as moyamoya disease and monogenic moyamoya syndromes, opening avenues to understanding the mysteries of their pathophysiology. 16,17 Finally, it is helpful to inform patients that conventional modifiable risk factors remain relevant, despite an unfavorable genetic background. The prospective, community-based Japan Collaborative Cohort Study, which involved >110 000 individuals, found that a parental history of stroke imparted a population-attributable fraction of risk of stroke death of 5.4% in men and 4.3% in women.…”