Computing the Pathogenicity of Wilson’s Disease ATP7B Mutations: Implications for Disease Prevalence

Abstract

Genetic variations in the gene encoding the copper-transport protein ATP7B are the primary cause of Wilson's disease. Controversially, clinical prevalence seems much smaller than prevalence estimated by genetic screening tools, causing fear that many people are undiagnosed although early diagnosis and treatment is essential. To address this issue, we benchmarked 16 state-of-the-art computational disease-prediction methods against established data of missense ATP7B mutations. Our results show that the quality of the methods vary widely. We show the importance of optimizing the threshold of the methods used to distinguish pathogenic from non-pathogenic mutations against data of clinically confirmed pathogenic and non-pathogenic mutations. We find that most methods use thresholds that predict too many ATP7B mutations to be pathogenic. Thus, our findings explain the current controversy on Wilson's disease prevalence, because meta analysis and text search methods include many computational estimates that lead to higher disease prevalence than clinically observed. Since proteins and diseases differ widely, a one-size-fits-all threshold cannot distinguish efficiently pathogenic and non-pathogenic mutations, as shown here. We also show that amino acid changes with small evolutionary substitution probability, mainly due to amino acid volume, are more associated with disease, implying a pathological effect on the conformational state of the protein, which could affect copper transport or ATP recognition and hydrolysis. These findings may be a first step towards a more quantitative genotype-phenotype relationship of Wilson's disease.

Prevalence of Wilson disease based on genome databases in Japan

“…24 This may be due to the inclusion of benign variants and the prediction of too many ATP7B mutations as pathogenic. 24 This could result from the lack of clear genotype-phenotype relations in WD patients. More research is therefore needed to distinguish disease-causing mutations from benign variants.…”

Direct Measurement of ATP7B Peptides Is Highly Effective in the Diagnosis of Wilson Disease

“…The definition of "disease"-causing variant is based on a variety of databases, which can give conflicting answers. 28 We hypothesized that direct measurement of ATP7B could identify WD patients as a majority of pathogenic mutations often result in protein misfolding, absence of decay of messenger RNA and enhanced degradation. To explore this goal, 2 WT ATP7B peptides were chosen for antipeptide antibody generation.…”

The pathophysiology of Wilson’s disease visualized: A human 64Cu PET study

“…[ 4 , 5 ] However, diagnosing WD can be challenging given that no clinical symptoms or laboratory tests (including genetic testing) can be used to exclude or diagnose WD with sufficient accuracy. [ 7 , 8 , 9 , 10 ] Accordingly, noninvasive methods to study the hepatic handling of copper are warranted to improve our understanding of the pathophysiology behind WD and assist the development of drugs and diagnostic tools.…”