CDC123 variants associated with developmental abnormalities alter CDC123-eIF2 subunit interactions and impair protein synthesis

Four pediatric families with neurodevelopmental delays, hypotonia, and motor dysfunction carry three novel heterozygous CDC123 missense variants that impair CDC123-eIF2 interactions and protein synthesis.

• Why it matters: The pathogenicity and cellular mechanisms of clinically reported CDC123 variants of uncertain significance are unexplored, despite eIF2’s essential role in development and physiology.
• What they did: The study assessed variant allele frequencies, conservation, structural modeling, and functional assays in humanized yeast and human cell-based model systems.
• The result: CDC123 variants were damaging to CDC123 activity, altered CDC123-eIF2 subunit interactions, reduced cell growth, and showed dominant-negative effects on yeast growth and protein synthesis.

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