De novo variant in RING finger protein 213 causes systemic vasculopathy.

Systemic arterial stenosis, including moyamoya disease (MMD) and middle aortic syndrome (MAS), is a rare condition of unclear etiology. MMD is a cerebral angiopathy, whereas MAS affects abdominal and thoracic aortas, leading to various complications. Although some genetic associations with MAS have been identified, the causes remain elusive. In this study, whole-exome sequencing was used to identify de novo heterozygous missense variants of RING finger protein 213 (RNF213) (p.His4058Pro and p.Thr4155Pro) in two unrelated families exhibiting both MAS and MMD. To understand the significance of these variants, we generated knockin mice carrying the Rnf213 p.His4058Pro variant. Notably, homozygous knockin mice exhibited perinatal lethality due to respiratory failure and lung dysplasia, suggesting that this variant is pathogenic. Lung dysplasia in homozygous knockin mice was associated with upregulated innate immunity and inflammatory responses and downregulated cell proliferation. The findings suggested that in mice, the RNF213 p.His4058Pro variant plays critical roles in lung development, innate immunity, and inflammation, revealing the complexity of RNF213 function in various tissues and species. In conclusion, this study provides insights into the genetic basis of MAS and MMD, highlights the potential involvement of RNF213 variants in systemic vasculopathy, and identifies unexpected associations with lung development and immune processes.