RNF213 – Moyamoya Disease

Ring finger protein 213 (RNF213) has been robustly implicated as the primary susceptibility gene for Moyamoya disease (MMD), a progressive steno-occlusive cerebrovascular disorder characterized by bilateral internal carotid artery narrowing and compensatory basal collateral formation. MMD shows geographic predilection for East Asians but occurs worldwide, with clinical manifestations ranging from transient ischemic attacks (TIAs) and ischemic strokes to intracranial hemorrhage and seizures.

A landmark genome-wide association study in 72 Japanese MMD patients identified the RNF213 p.Arg4810Lys variant (c.14429G>A) in 95% of familial and 73% of sporadic cases (OR 190.8) (PMID:21048783). Homozygous carriers exhibit earlier onset (median 3 y) and more severe infarctions compared with heterozygotes and wild-type individuals (PMID:22377813). Additional rare RNF213 missense variants have been described in non-East Asian families (e.g., p.Lys4185Glu and p.Ala4188Thr) and de novo cases, expanding the mutational spectrum.

Segregation analyses demonstrate incomplete penetrance: among 59 relatives of 18 index patients, 34 heterozygotes for p.Arg4810Lys were identified and 8 developed steno-occlusive intracranial lesions (23.5%) by follow-up angiography (PMID:28506590). Homozygosity increases both penetrance and severity, supporting a dose-dependent effect of the variant on clinical phenotype.

Functional studies reveal that Moyamoya-associated RNF213 RING domain mutations markedly reduce E3 ubiquitin ligase activity toward K63-linked polyubiquitin chains while enhancing NFκB activation and apoptosis in an AAA+ ATPase-dependent manner, consistent with endothelial dysfunction and aberrant angiogenesis (PMID:32139119). In vascular models, RNF213 variants aggravate hypoxia-induced pulmonary hypertension, underscoring systemic vasculopathy beyond the cerebral circulation (PMID:29718794).

Collectively, the definitive gene-disease relationship between RNF213 and MMD is supported by robust genetic association across >1000 probands, segregation in multiple families, and concordant functional evidence demonstrating disrupted ubiquitin signaling and vascular homeostasis. RNF213 genetic testing informs risk stratification, guides family screening, and may direct early revascularization strategies to prevent irreversible deficits.

Key Take-home: RNF213 p.Arg4810Lys is the major Moyamoya disease allele, with homozygosity predicting early-onset, severe arteriopathy; genetic screening is clinically actionable for diagnosis and management.

References

• Journal of human genetics • 2011 • A genome-wide association study identifies RNF213 as the first Moyamoya disease gene. PMID:21048783
• Neurology • 2012 • Homozygous c.14576G>A variant of RNF213 predicts early-onset and severe form of moyamoya disease. PMID:22377813
• Journal of stroke and cerebrovascular diseases • 2017 • RNF213 p.R4810K Variant and Intracranial Arterial Stenosis or Occlusion in Relatives of Patients with Moyamoya Disease. PMID:28506590
• Biochemical and biophysical research communications • 2020 • Moyamoya disease patient mutations in the RING domain of RNF213 reduce its ubiquitin ligase activity and enhance NFκB activation and apoptosis in an AAA+ domain-dependent manner. PMID:32139119
• Pulmonary circulation • 2018 • Rare variants in RNF213, a susceptibility gene for moyamoya disease, are found in patients with pulmonary hypertension and aggravate hypoxia-induced pulmonary hypertension in mice. PMID:29718794

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