The RNF213 gene, also known as Ring Finger Protein 213, provides instructions for making a large protein. This protein is found in various tissues throughout the body. Variations within this gene are associated with certain health conditions, particularly those affecting blood vessels.
The Normal Role of RNF213
The RNF213 protein, a large intracellular protein, contains specific regions indicating its functions. It possesses a RING finger domain, which identifies it as an E3 ubiquitin ligase. These enzymes tag other proteins with ubiquitin, marking them for degradation or altering their function. This process regulates proteins, removing damaged or unnecessary ones and maintaining cellular health.
The RNF213 protein also includes two AAA+ ATPase domains. Proteins with these domains regulate mechanical processes within cells, such as protein unfolding or molecule transport. Studies suggest that the RNF213 protein plays a part in blood vessel development, influencing processes like angiogenesis (the formation of new blood vessels). It has also been linked to lipid metabolism and the cellular response to low oxygen levels.
RNF213 and Moyamoya Disease
The RNF213 gene is strongly associated with Moyamoya disease, a rare cerebrovascular disorder. Moyamoya disease involves the progressive narrowing and occlusion of arteries at the base of the brain, particularly the internal carotid arteries and their branches. As these main vessels constrict, the brain compensates by developing a network of small, fragile collateral blood vessels. On angiography, these new vessels appear as a “puff of smoke,” which is what “moyamoya” means in Japanese.
RNF213 is recognized as the primary susceptibility gene for Moyamoya disease, especially prevalent in East Asian populations. A specific variant, p.R4810K, is strongly linked to the disease in Japanese, Korean, and Chinese individuals, indicating a significantly increased risk. While more common in East Asia, RNF213 variations are also identified in some Western cases. The disease has two incidence peaks: one in children around 5 years of age and another in adults in their mid-40s.
How RNF213 Mutations Affect Health
Mutations in the RNF213 gene contribute to conditions like Moyamoya disease by altering the protein’s normal functions. The most common variant, p.R4810K, involves a single amino acid change, replacing arginine with lysine. These changes are thought to interfere with the RNF213 protein’s role in vascular health.
One leading hypothesis suggests that altered RNF213 function impairs angiogenesis, leading to abnormal blood vessel development and remodeling, and can promote pathological angiogenesis. This can result in abnormal proliferation and migration of smooth muscle cells within blood vessels, contributing to the characteristic narrowing and occlusion seen in Moyamoya disease. The mutation may also affect protein degradation pathways, leading to the accumulation of proteins involved in vessel development.
Diagnosis and Management of RNF213-Related Conditions
Diagnosing conditions linked to RNF213, such as Moyamoya disease, involves a combination of genetic testing and detailed imaging techniques. Genetic testing can identify specific RNF213 variants. For Moyamoya disease, the presence of the p.R4810K variant is a strong indicator, though other rare variants can also be identified.
Imaging techniques are crucial for assessing vascular changes and confirming the diagnosis. Magnetic Resonance Imaging (MRI) and Magnetic Resonance Angiography (MRA) are frequently used to visualize the brain’s blood vessels, showing stenosis or occlusion of the internal carotid arteries and the characteristic “puff of smoke” appearance of collateral vessels. Computed Tomography (CT) scans and CT angiography also provide detailed images of the brain and its vasculature. Cerebral angiography, which involves injecting a dye into blood vessels for X-ray imaging, offers a highly detailed view of blood flow and vessel abnormalities.
Management strategies for RNF213-related conditions, particularly Moyamoya disease, aim to prevent complications like stroke and improve blood flow to the brain. Medical treatments include medications to manage symptoms or reduce the risk of stroke. Blood thinners like aspirin may be prescribed to prevent blood clots. Calcium channel blockers can help manage headaches and reduce symptoms of transient ischemic attacks.
Surgical interventions are often considered to improve cerebral blood flow. Direct revascularization procedures, such as superficial temporal artery to middle cerebral artery (STA-MCA) bypass, involve directly connecting an artery from outside the brain to an artery inside the brain to reroute blood flow. Indirect revascularization techniques, like synangiosis, involve placing vascularized tissue on the brain’s surface to encourage the growth of new blood vessels over time. These approaches aim to augment intracranial blood supply and prevent further neurological damage.