The RNF213 gene encodes a cytosolic protein consisting of a RING finger domain and two AAA+ ATPase domains. The protein possesses E3 ubiquitin ligase activity and ATPase activity and it specifically targets FLNA and NFATC2 downstream of RSPO3 for ubiquitination and subsequent degradation. This leads to the inhibition of the non-canonical Wnt signaling pathway involved in vascular development. The protein thus plays a key role in angiogenesis, particularly in sprouting angiogenesis.
Genome wide association studies have helped identify a link between RNF213 mutations and susceptibility to Moyamoya Disease 2, a disorder characterized by intracranial carotid artery occlusion, basal ganglia telangiectases and inflammatory arteriopathy. Animal studies have helped reinforce the role of the protein in vascular growth; knockdown of the RNF213 ortholog in zebrafish has been found to result in abnormal vascular development, notably causing deficient sprouting vessels in the head.
The RNF213 gene is located on the long arm of chromosome 17. It spans a length of 137.9 kb of DNA and its coding sequence is spread across 73 exons. The gene encodes a 591.4 kDa protein product composed of 5207 amino acids. Several additional isoforms of the RNF213 protein exist due to alternatively spliced transcript variants. The gene is widely expressed in the human body.
Around 24 mutations in the RNF213 gene have been associated with Moyamoya disorder. These are mainly missense mutations with p.Arg4810Lys being the most commonly identified variant. A translocation resulting in the fusion of RNF213 with the ALK gene has also been found. The fusion gene has been associated with ALK-positive anaplastic large-cell lymphoma.
Monies et al. (2017) examined the genomic landscape of Saudi Arabia based on the findings of 1000 diagnostic panels and exomes. One patient, an 18-year-old male with autism spectrum disorder was subjected to whole exome sequencing. This helped identify a heterozygous mutation (c.14394delC, p.F4798fs) in exon 60 of the patient’s RNF213 gene. This gene mutation was considered a candidate for pathogenicity as it was a novel variant predicted to be deleterious; and the gene had been associated with CNS vascular malformation. The authors noted that further studies are required to confirm this association.