De novo variant in RING finger protein 213 causes systemic vasculopathy

Area of Science:

• Genetics
• Vascular Biology
• Immunology

Background:

• Systemic arterial stenosis, including moyamoya disease (MMD) and middle aortic syndrome (MAS), are rare conditions with unknown causes.
• While genetic links to MAS exist, the precise etiology remains elusive.
• RNF213 gene variants have been implicated in MMD, but their role in other systemic vasculopathies is less understood.

Purpose of the Study:

• To investigate the role of de novo heterozygous missense variants in RING finger protein 213 (RNF213) in patients with MMD and MAS.
• To elucidate the functional significance of identified RNF213 variants using a mouse model.

Main Methods:

• Whole-exome sequencing was performed on two families with co-occurring MMD and MAS.
• Knockin mice carrying the Rnf213 p.His4058Pro variant were generated to study its effects in vivo.
• Analysis of lung development, immune responses, and cell proliferation in homozygous knockin mice.

Main Results:

• De novo heterozygous missense variants (p.His4058Pro and p.Thr4155Pro) in RNF213 were identified in patients with MAS and MMD.
• Homozygous Rnf213 p.His4058Pro knockin mice exhibited perinatal lethality due to respiratory failure and lung dysplasia.
• Lung dysplasia in mice was characterized by upregulated innate immunity and inflammation, alongside decreased cell proliferation.

Conclusions:

• The study provides evidence for the pathogenic role of RNF213 p.His4058Pro variants in systemic vasculopathy.
• RNF213 variants are implicated in the genetic basis of MAS and MMD.
• These findings reveal an unexpected link between RNF213 function, lung development, and immune regulation, highlighting the complexity of RNF213 in different tissues and species.