ATP7B – Wilson Disease

ATP7B encodes a copper-transporting P-type ATPase essential for hepatic biliary copper excretion. Biallelic pathogenic variants in ATP7B disrupt copper homeostasis, causing Wilson disease, an autosomal recessive disorder characterized by hepatic copper overload and secondary neurological injury. Symptom onset varies from childhood to adulthood, with presentations ranging from fulminant hepatic failure to movement disorders such as tremor and dystonia (HP:0001394) (PMID:9504786).

Genetic evidence includes identification of over 300 disease-associated variants across more than 200 unrelated probands, including >20 novel mutations per population study (PMID:15967699). The common European founder allele c.3207C>A (p.His1069Gln) accounts for ~35–60% of WD chromosomes (PMID:9311736). Segregation analyses in multiple families demonstrate autosomal recessive inheritance with compound heterozygosity or homozygosity for pathogenic variants in affected sibships (≥7 additional affected relatives identified). Case reports detail frameshift alleles such as c.213_214del (p.Val73fs) leading to absent functional protein and early-onset severe phenotype (PMID:9504786).

Functional assays support loss-of-function as the mechanism of pathogenicity. Yeast complementation of ccc2 mutants shows that missense variants retain partial copper transport activity, whereas truncating and splice-site mutations abrogate activity, confirmed by reduced copper-stimulated ATPase in patient lymphoblasts (PMID:9837819). Cellular studies reveal that certain missense mutants are mislocalized and fail to traffic from the trans-Golgi network in response to copper, while others disrupt ATOX1-mediated copper delivery to the N-terminal metal-binding domain (PMID:12029094).

Some variants display atypical behavior: for example, the p.Pro1379Ser allele exhibits reduced steady-state ATP7B levels yet maintains sufficient activity to prevent clinical WD, indicating potential benign variation (PMID:32685348). Additionally, the exon 1 frameshift c.19_20del (p.Gln7fs) can bypass nonsense-mediated decay via downstream translation reinitiation, resulting in a partially functional protein and no overt phenotype (PMID:30723317).

Collectively, genetic and experimental data definitively establish ATP7B loss-of-function as the cause of Wilson disease. The spectrum of pathogenic variants encompasses missense, nonsense, frameshift, splice-site, and complex indels, with strong genotype–phenotype correlations for truncating alleles linked to early-onset hepatic disease. Functional characterization of individual variants informs variant classification and genetic counseling. Key take-home: early molecular diagnosis of ATP7B mutations enables prompt chelation therapy and improved clinical outcomes.

References

• American Journal of Human Genetics • 1997 • Identification and analysis of mutations of the Wilson disease gene in North American patients PMID:9311736
• Molecular Genetics and Metabolism • 2005 • Mutation analysis of the ATP7B gene and genotype/phenotype correlation in 227 patients with Wilson disease PMID:15967699
• European Journal of Pediatrics • 1998 • Early and severe neurological features in a Wilson disease patient compound heterozygous for two frameshift mutations PMID:9504786
• American Journal of Human Genetics • 1998 • Functional characterization of missense mutations in ATP7B: Wilson disease mutation or normal variant? PMID:9837819
• Journal of Biological Chemistry • 2002 • Metallochaperone Atox1 transfers copper to the NH2-terminal domain of the Wilson's disease protein PMID:12029094
• JIMD Reports • 2020 • p.P1379S, a benign variant with reduced ATP7B protein level in Wilson Disease PMID:32685348
• European Journal of Human Genetics • 2019 • Homozygous frame shift variant in ATP7B exon 1 leads to bypass of nonsense-mediated mRNA decay PMID:30723317

Evidence Based Scoring (AI generated)