Valeriya Vinokurova

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.

Background/Objectives: Wilson’s disease (WD) (OMIM 277900) or hepatolenticular degeneration is an autosomal recessive disorder caused by impaired copper excretion with subsequent accumulation in the liver, brain, and other tissues of the body. The defects in copper metabolism are based on various pathogenic variants of the ATP7B gene encoding copper-transporting P-type ATPase. The aim of this work is to search for pathogenic variants of the ATP7B gene among Eastern Eurasian patient cohorts and to pick correlations between pathogenic variants, gender, age of onset of the disease, and the course of the disease. Methods: The material for the study was the biomaterial of 100 people. The search for mutations was carried out by Sanger sequencing. Multiple alignment of nucleotide sequences and their analysis was performed using the MEGA-X software. To study the genotype-phenotypic correlation, an analysis of the medical records of each patient was carried out. Results: Most common pathogenic variant (48%) in the sample is p.His1069Gln (c.3207C>A), located in exon 14 of the ATP7B gene. Pathogenic variants of p.Glu1064Lys (c.3190G>A)—20%—and p.Met769HisfsTer26 (c.2304insC)—8%—of exons 14 and 8 were also common. For patients with pathogenic alleles p.His1069Gln (c.3207C>A) and p.Glu1064Lys (c.3190G>A), typical deviations are mental and neurological manifestations of WD. In patients with the pathogenic allele p.Met769HisfsTer26 (c.2304insC), deviations are more characteristic of the liver and a combination of various symptoms that are atypical for WD. Conclusions: In this study, we were able to obtain differences in symptoms in patients with different pathogenic alleles of the ATP7B gene.