The genetics of Wilson disease

Abstract

Wilson disease (WD) is an autosomal-recessive disorder of hepatocellular copper deposition caused by pathogenic variants in the copper-transporting gene, ATP7B. Early detection and treatment are critical to prevent lifelong neuropsychiatric, hepatic, and systemic disabilities. Due to the marked heterogeneity in age of onset and clinical presentation, the diagnosis of Wilson disease remains challenging to physicians today. Direct sequencing of the ATP7B gene is the most sensitive and widely used confirmatory testing method, and concurrent biochemical testing improves diagnostic accuracy. More than 600 pathogenic variants in ATP7B have been identified, with single-nucleotide missense and nonsense mutations being the most common, followed by insertions/deletions, and, rarely, splice site mutations. The prevalence of Wilson disease varies by geographic region, with higher frequency of certain mutations occurring in specific ethnic groups. Wilson disease has poor genotype-phenotype correlation, although a few possible modifiers have been proposed. Improving molecular genetic studies continue to advance our understanding of the pathogenesis, diagnosis, and screening for Wilson disease.

Keywords: ATP7B; Wilson disease; copper metabolism; molecular diagnosis.

Fig. 3.1

Schematic representation of copper-induced relocalization of ATP7A and ATP7B. The left side of the diagram represents an enterocyte and the right side represents a hepatocyte. On both sides, copper enters the cell through copper transporter 1 (CTR1) and is escorted by copper chaperone antioxidant protein 1 (ATOX1) to ATP7A or ATP7B in the trans-Golgi network (TGN). When copper levels rise above a certain threshold, ATP7A and ATP7B excrete copper into the plasma on the basolateral side of the enterocyte and into the bile on the apical side of the hepatocyte. Defects in localization of ATP7B may lead to copper accumulation at the (1) TGN due to unresponsiveness, (2) cell periphery, and (3) endoplasmic reticulum (ER) due to misfolding. (Reproduced from de Bie et al., 2007.)

Fig. 3.2

Schematic representation of ATP7B gene and corresponding human ATP7B protein. Top diagram shows 5’UTR promoter region and exons separated by introns. Bottom diagram shows the domain organization of human copper ATPase. Conserved amino acid motifs are present at the core structure of each functional domain, i.e., TGDN and GDGVND at the A-domain, DKTG at the P-domain, and SEHPL in the N-domain. M, phospholipidic bilayer of the membrane; Cu, the metal-binding domains of the trasmembrane cation channel; Tm, transmembrane domains; PD, phosphatase domain. (Reproduced from Fanni et al., 2005.)

Fig. 3.3

Schematic of the ATP7B gene with common mutation sites, including p.H1069Q (rs76151636), p.R778L (rs28942074), p.E1064K (rs376910645), c.3400delC, and p.Ala1135fs (rs137853281). Please refer to Table 3.1 for more details.

Fig. 3.4

Prevalence of ATP7B mutation by geographic region; the darker the gradient, the higher the allelic frequency. (Reproduced from Gomes and Dedoussis, 2016, with permission from Taylor and Francis.)