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DNAJC12 p.Asp44Gly associated with mild hyperphenylalaninemia and migraine-like headaches: Structural and deep
Jie Zhang1, Binghe Xiao2, Zhiliang Wang2
1Department of Rehabilitation, Huashan Hospital of Fudan University, Shanghai, China.
Insights
DNAJC12 deficiency causes hyperphenylalaninemia. A deep learning approach suggests the D44G variant may impact DNAJC12 function, but further validation is needed for pathogenicity.
Area of Science:
- Genetics
- Molecular Biology
- Biochemistry
Background:
- DNAJC12 encodes a J-domain co-chaperone crucial for aromatic amino acid hydroxylase function.
- DNAJC12 deficiency is linked to hyperphenylalaninemia (HPA) and neurotransmitter deficits.
- A 19-year-old male presented with mild HPA, headaches, and white matter changes, prompting investigation of a DNAJC12 variant.
Purpose of the Study:
- To assess the pathogenicity of the DNAJC12 c.131A>G (p.Asp44Gly, D44G) variant using an integrated deep learning (DL) approach.
- To evaluate the impact of D44G and four other reported missense variants on DNAJC12 protein function and structure.
- To provide clinical and genetic evidence for DNAJC12-related disorders.
Main Methods:
- Integrated DL-based and conventional algorithms (AlphaFold2, AlphaMissense, REVEL, PolyPhen-2, ThermoMPNN) for variant analysis.
- Principal Component Analysis (PCA) to characterize pathogenicity metrics at different levels (overall, position, substitution).
- Classification of variant significance following ACMG and ClinGen standards.
Main Results:
- The Asp44 residue is located within the conserved His-Pro-Asp motif of the DNAJC12 J-domain.
- Missense variants, including D44G, may alter predicted side-chain interactions and thermodynamic stability.
- PCA indicated D44G's predicted deleteriousness aligns with strong position-specific constraint, classifying it as a variant of uncertain significance (VUS).
Conclusions:
- Findings support a potential functional impact of the D44G variant in DNAJC12-related disease, but pathogenicity is not yet established.
- DNAJC12 should be considered in genetic evaluations for unexplained HPA with neurological symptoms.
- The D44G variant requires further functional validation to confirm its clinical significance.
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 constraint. D44G was classified as a variant of uncertain significance (PM1, PM2_Supporting, and PP3_Supporting).
Conclusion:
Our findings provide additional clinical and genetic evidence relevant to DNAJC12-related disease and support a potential functional effect of D44G, but do not establish its pathogenicity yet. DNAJC12 should be included in the genetic evaluation of patients with unexplained HPA with neurological manifestations, and D44G warrants further functional validation.
