rs28942074 — ATP7B R778L

ATP7B R778L — The East Asian Wilson Disease Variant

Copper is an essential mineral — a cofactor for enzymes involved in energy production, antioxidant defence, and neurotransmitter synthesis — yet it is toxic when it accumulates. The liver is the body's copper thermostat: it absorbs dietary copper from the portal circulation, uses what is needed, loads the rest onto the plasma protein ceruloplasmin¹¹ ceruloplasmin
The main copper-carrying protein in blood; synthesised in the liver as apo-ceruloplasmin and activated when ATP7B loads copper onto it before secretion. Low serum ceruloplasmin is a hallmark diagnostic marker of Wilson disease. Approximately 95% of plasma copper is bound to ceruloplasmin., and exports any surplus into bile for elimination. ATP7B, encoded on chromosome 13, is the transmembrane P-type ATPase responsible for both of these functions. When both copies of ATP7B are non-functional, copper cannot leave the liver — and Wilson disease²² Wilson disease
A rare autosomal recessive disorder of copper metabolism first described by neurologist Samuel Alexander Kinnier Wilson in 1912. Estimated prevalence 1 in 30,000; carrier frequency approximately 1 in 90. follows.

The R778L variant (p.Arg778Leu, c.2333G>T) replaces arginine with leucine at amino acid position 778 in the ATP-binding domain of ATP7B. Identified as ClinVar Pathogenic variant VCV000003852, it is the most common Wilson disease mutation across East Asia, accounting for 28.96% of all pathogenic ATP7B alleles³³ accounting for 28.96% of all pathogenic ATP7B alleles
Zhang et al. 2022, Translational Neurodegeneration, cohort of 1,302 Chinese Wilson disease patients in Chinese patients — and for approximately 17% of alleles in Hong Kong Chinese, where haplotype analysis reveals a single ancestral founder at least 5,500 years old⁴⁴ where haplotype analysis reveals a single ancestral founder at least 5,500 years old
Mak et al. 2008, J Hum Genet.

The Mechanism

The ATP7B gene lies on the minus strand of chromosome 13. At GRCh38 position 13:51,958,333, the plus-strand reference nucleotide is C (corresponding to coding-strand G = arginine at position 778). The pathogenic alternate allele is A on the plus strand (coding-strand T = leucine substitution). Both WGS and consumer genotyping chips report alleles on the plus strand, so the wild-type homozygote appears as CC and the risk homozygote as AA.

Arginine 778 sits within the ATP-binding domain, a region essential for the phosphorylation cycle that drives copper translocation across the membrane. The arginine-to-leucine substitution does not merely reduce enzymatic efficiency — it fundamentally mislocalises the protein⁵⁵ mislocalises the protein
Zhu et al. 2015, Mol Cell Neurosci, showed R778L uniquely disrupts BOTH subcellular localization AND vesicular trafficking of ATP7B, while P992L only disrupts trafficking; the mutant protein fails to reach the trans-Golgi network where copper loading onto ceruloplasmin occurs. The ATP7B protein cannot reach its functional destination. As a consequence, copper accumulates in hepatocytes, ceruloplasmin secretion falls, and biliary copper excretion is abolished.

In R778L homozygous iPSC-derived hepatocytes, ATP7B protein expression and ceruloplasmin secretion are both reduced compared to controls⁶⁶ ATP7B protein expression and ceruloplasmin secretion are both reduced compared to controls
Song et al. 2022, Hum Mol Genet; partial genetic correction (heterozygous CRISPR repair) restores ceruloplasmin expression, suggesting even one functional allele is sufficient to maintain near-normal copper handling. This haploinsufficiency threshold is why heterozygous carriers are clinically unaffected.

The Evidence

Clinical disease follows copper accumulation in a predictable sequence. Hepatic copper overload causes liver inflammation and fibrosis, sometimes presenting as acute hepatitis or cirrhosis in children and young adults. Copper eventually spills into the systemic circulation and deposits in the brain (causing movement disorders, cognitive changes, and psychiatric symptoms), the cornea (Kayser-Fleischer rings — the pathognomonic brown-gold deposits at the corneal periphery), and the kidneys (Fanconi syndrome). In a meta-analysis of 3,007 Chinese Wilson disease patients across 23 studies⁷⁷ meta-analysis of 3,007 Chinese Wilson disease patients across 23 studies
Xue et al. 2023, Pediatr Neurol, R778L carriers presented at a significantly younger age (SMD -0.18, p=0.0004) and had lower serum ceruloplasmin concentrations (SMD -0.21, p=0.03) than non-R778L carriers, consistent with the mutation's severe trafficking defect.

A knock-in mouse model carrying R778L confirmed the liver-to-brain disease pathway: by 3-5 months, mice show motor and cognitive dysfunction driven by hepatic copper overload that triggers systemic neuroinflammation (microglial activation, elevated cytokines), not by direct copper accumulation in brain tissue⁸⁸ by 3-5 months, mice show motor and cognitive dysfunction driven by hepatic copper overload that triggers systemic neuroinflammation (microglial activation, elevated cytokines), not by direct copper accumulation in brain tissue
Dong et al. 2024, J Neuroinflammation; pharmacological inhibition of hepatic NF-κB normalized cognitive and motor performance, implicating the liver-brain inflammatory axis as the primary driver of neurological symptoms.

Wilson disease is eminently treatable when diagnosed before end-organ damage sets in. EASL-ERN 2025 guidelines⁹⁹ EASL-ERN 2025 guidelines
European Association for the Study of the Liver / European Reference Network clinical practice guidelines, J Hepatol 2025 recommend copper chelation (D-penicillamine or trientine) as first-line therapy for hepatic disease, with zinc salts for maintenance or neurological presentations. Liver transplantation is indicated for acute hepatic failure and is curative for the hepatic component of the disease.

Practical Actions

For heterozygous carriers (AC genotype): one functional ATP7B copy is sufficient for normal copper metabolism. No dietary copper restriction or medical treatment is needed. The clinical priority is family planning — if a reproductive partner also carries an ATP7B pathogenic variant, there is a 25% chance per pregnancy that a child will inherit two non-functional copies and develop Wilson disease. Carrier testing of partners and genetic counselling are strongly recommended before conception.

For homozygotes and compound heterozygotes (AA genotype or compound AA with another ATP7B pathogenic variant): Wilson disease should be assumed to be present or imminent. Specialist hepatology evaluation, confirmatory biochemical testing (serum ceruloplasmin, 24-hour urinary copper, liver copper), slit-lamp examination, and neurological assessment are urgent. Lifelong copper-lowering therapy must begin as early as possible — early treatment before symptomatic organ damage prevents all major complications.

Interactions

ATP7B R778L interacts with other pathogenic ATP7B variants in compound heterozygosity — the most common mode of Wilson disease in East Asian patients. Common compound genotypes include R778L/P992L and R778L/A874V. In the Zhang et al. 2022 cohort, R778L/A874V compound heterozygotes had later onset than R778L/R778L homozygotes, suggesting A874V is a partial-function allele. Carriers of R778L who are compound heterozygous with a severe truncating variant (frameshift, splice site) tend to present earliest. The related ATP7B variant rs201038679 (P992L) is the second most common Wilson disease mutation in East Asian populations; rs137853280 (c.1708-1G>C, a splice-acceptor variant) is a common pathogenic allele in European populations. Any of these, when compound-heterozygous with R778L, results in Wilson disease with severity depending on residual function of the trans-allele protein.