Localization of Pathogenic Variants in the Structure of the ATP7B Gene Defines Distinct Clinical Outcomes in Wilson’s Disease

Background: Wilson’s disease (WD, OMIM: 277900) is a rare autosomal recessive genetic disorder characterized by abnormal copper accumulation, manifesting as a variety of symptoms, including hepatocellular, neuropsychiatric, and mixed manifestations. Defects in copper metabolism are caused by various pathogenic variants of the ATP7B gene, which encodes the copper-transporting P-type ATPase. The aim of this study was to establish a correlation between various clinical outcomes and the localization of pathogenic variants in the structure of the ATP7B gene. Methods: A total of 139 unrelated patients with suspected Wilson’s disease from Primorsky Krai, Khabarovsk Krai, Kamchatka and Sakhalin were included. ATP7B pathogenic variants were screened using Sanger sequencing. Medical records of each patient were analyzed to investigate genotype–phenotype correlations. Molecular modeling of the protein folding was performed for the most frequent pathogenic variants. Results: The most common ATP7B pathogenic variants were p.His1069Gln (c.3207C>A) (0.23) and p.Glu1064Lys (c.3190G>A) (0.115) in exon 14, followed by p.Met769HisfsTer26 (c.2304insC) (0.072) in exon 8. An analysis of the clinical outcomes and structural modeling of the protein variants of ATP7B revealed that pathogenic variants localized in transmembrane domain 2 (TM2) lead to protein destabilization and cause more severe symptoms. Patients with pathogenic variants in TM2 are characterized by paroxysmal seizures, Kayser–Fleischer rings, liver changes on ultrasound examination, and other symptoms atypical for Wilson’s disease. Pathogenic variants localized in the N-domain of ATP7B cause less severe structural changes. These abnormalities have less severe consequences than those associated with pathogenic variants in TM2. Patients with pathogenic variants in the N-domain exhibited hyperkinesia, brain pathology, and severe impairment of mental, intellectual, and cognitive functions. Conclusions: This study demonstrates that the phenotypic manifestations of the disease may depend on the localization of the pathogenic variant.