DNAJC12 p.Asp44Gly associated with mild hyperphenylalaninemia and migraine-like headaches: Structural and deep learning analyses
Abstract
Objective DNAJC12 encodes a J-domain co-chaperone involved in the function of aromatic amino acid hydroxylases, and its deficiency is associated with hyperphenylalaninemia (HPA) and monoamine neurotransmitter deficiency. We assessed a DNAJC12 c.131A > G (p.Asp44Gly, D44G) variant identified in a 19-year-old man who presented with mild HPA, recurrent migraine-like headaches, and phenylketonuria-like white matter changes, along with four reported clinically relevant missense variants (A62E, R72P, H102Q, and W103C), using an integrated deep learning (DL)-based approach. Methods DL-based and conventional prediction algorithms were integrated to evaluate the clinical and genetic findings, together with protein structural and pathogenic impact. Analyses incorporated AlphaFold2, AlphaMissense, REVEL, PolyPhen-2, and ThermoMPNN. Principal component analysis (PCA) was used to characterize overall, position-level, and substitution-level pathogenicity metrics. Pathogenicity classification followed American College of Medical Genetics and Genomics and ClinGen Sequence Variant Interpretation standards. Results The J-domain was confidently modeled, and Asp44 was located within the conserved His-Pro-Asp motif. DNAJC12 missense variants may affect predicted side-chain interactions and residue-contact patterns with thermodynamic changes. PCA of aggregated pathogenicity metrics indicated that the predicted deleteriousness of p.Asp44Gly was consistent with stronger position-specific…
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