Exome Sequencing Identified CCER2 as a Novel Candidate Gene for Moyamoya Disease

Area of Science:

• Genetics
• Neurology
• Molecular Biology

Background:

• The genetic basis of Moyamoya disease (MMD) remains largely unknown, with RNF213 being the primary identified susceptibility gene in East Asian populations.
• Previous research indicated genetic heterogeneity in Japanese MMD patients, prompting further investigation into novel candidate genes.

Purpose of the Study:

• To explore novel candidate genes contributing to the etiology of Moyamoya disease (MMD) in individuals without RNF213 susceptibility variants.
• To investigate the role of the CCER2 gene in MMD pathogenesis and its potential as a diagnostic biomarker.

Main Methods:

• Whole-exome sequencing was performed on two pedigrees with MMD and no RNF213 variants, including one with multiple affected members and another with discordant monozygotic twins.
• In silico functional analysis was used to predict the impact of identified CCER2 mutations on protein function.
• CCER2 gene re-sequencing was conducted in an additional cohort of 135 MMD probands.

Main Results:

• Twelve rare mutations in 12 different genes were found to co-segregate with MMD in one pedigree.
• Deleterious mutations in the CCER2 gene, including p.T76_G80delinsPS and p.E242K, were identified in both pedigrees, with evidence of reduced penetrance in one case.
• Additional CCER2 mutations (recurrent p.T76_G80delinsPS, p.H218_H220del, and p.E299del) were found in 135 MMD probands, suggesting CCER2 as a novel MMD-associated gene.

Conclusions:

• Mutations in the CCER2 gene represent a novel genetic factor contributing to Moyamoya disease (MMD) etiology, particularly in patients negative for RNF213 variants.
• Predicted functional consequences of CCER2 mutations suggest a role in protein aggregation or oligomerization.
• CCER2, a brain-expressed secretory protein, shows potential as a novel biomarker for Moyamoya disease (MMD).