Gene-specific features enhance interpretation of mutational impact on acid α-glucosidase enzyme activity

Abstract

We present a computational model for predicting mutational impact on enzymatic activity of human acid α-glucosidase (GAA), an enzyme associated with Pompe disease. Using a model that combines features specific to GAA with other general evolutionary and physiochemical features, we made blind predictions of enzymatic activity relative to wildtype human GAA for >300 GAA mutants, as part of the Critical Assessment of Genome Interpretation 5 GAA challenge. We found that gene-specific features can improve the performance of existing impact prediction tools that mostly rely on general features for pathogenicity prediction. Majority of the poorly predicted mutants that lower wildtype GAA enzyme activity occurred on the surface of the GAA protein. We also found that gene-specific features were uncorrelated with existing methods and provided orthogonal information for interpreting the origin of pathogenicity, particular in variants that are poorly predicted by existing general methods. Specific variants in GAA, when investigated in the context of its protein structure, suggested gene-specific information like the disruption of local backbone torsional geometry and disruption of particular sidechain-sidechain hydrogen bonds as some potential sources for pathogenicity.

Keywords: Pompe disease; acid α-glucosidase; enzyme activity prediction; gene-specific variant effect prediction; variant interpretation.

Figure 1:

Scatterplot matrix showing correlation between of one of our prediction models (AA_4) to some other existing pathogenicity prediction tools (REVEL, MetaSVM, MutPred) as well as the experimental % wildtype GAA mean activity (MeanActivity) from the CAGI 5 GAA challenge.

Figure 2:

Left: Location in the protein structure (PDB: 5kzw) of the human GAA variants from the CAGI5 GAA challenge with <10% experimental wildtype enzyme activity. Variants correctly predicted to have <10% wildtype activity by our model (AA_1) are shown in green and those failed to be identified are shown in red. Right: For different binary prediction outcome categories for classifying variants that result in <10% experimental wildtype enzyme activity, box plots showing Cβ atom distances of the mutated amino acid site to the protein core

Figure 3:

Within variants resulting in <10% wildtype enzyme activity values in the experimental data, absolute Pearson correlation coefficient of the various features with the experimental values. Gene-specific features are shown in blue and general features are shown in green.

Figure 4:

For variants where prior enzyme activity data was available (in our training set), the corresponding experimental % wildtype enzyme activity values in the CAGI5 GAAGAA challenge dataset are plotted.

Figure 5:

A sidechain-sidechain hydrogen bond is disrupted by a GAAGAA variant. In the wildtype GAAGAA protein, the NH1 atom of the Arg464 sidechain forms a hydrogen bond with the OD2 atom of Asp501. The NP_000143.2:p.Arg464Ser variant results in the loss of the hydrogen bonding partner for Asp502 sidechain.