2.1. Moyamoya disease

At least 24 genetic changes in the RNF213 gene have been associated with moyamoya disease. This condition is characterized by narrowing of blood vessels in the brain and subsequent growth of networks of small, fragile blood vessels. The resulting lack of blood flow in the brain leads to strokes and other features of the condition.

Changes in the RNF213 gene involved in moyamoya disease replace single protein building blocks (amino acids) in the RNF213 protein. The most common change is a normal variation (polymorphism) of the gene that replaces the amino acid arginine with the amino acid lysine at protein position 4810 (written as Arg4810Lys or R4810K). This genetic change is found in a majority of affected individuals in Asian populations and is relatively common in unaffected individuals in these populations, occurring in about 1 percent. (This phenomenon, in which people with an altered copy of the gene never develop the condition, is known as reduced penetrance.) However, the Arg4810Lys change is not found in affected individuals of European descent. These individuals have rarer RNF213 gene mutations that change single amino acids in the protein.

Little is known about the effect of these changes on the function of the RNF213 protein, and researchers are unsure how the changes contribute to the characteristic blood vessel abnormalities of moyamoya disease. It is unclear if RNF213 gene mutations are involved in the narrowing of blood vessels in the brain. For unknown reasons, people with moyamoya disease have elevated levels of proteins involved in cell and tissue growth, including the growth of blood vessels (angiogenesis). An excess of these proteins could account for the growth of new blood vessels characteristic of moyamoya disease. It is not clear if changes in the RNF213 gene are involved in the overproduction of these proteins.

Little is known about the cause of moyamoya disease. Studies suggest that other genes could be involved in development of the condition. It has been suggested that other factors, such as infection or inflammation, in combination with genetic changes may be necessary for development of moyamoya disease.