Alternative titles; symbols
HGNC Approved Gene Symbol: ATP7B
SNOMEDCT: 190823004, 88518009; ICD10CM: E83.01;
Cytogenetic location: 13q14.3 Genomic coordinates (GRCh38): 13:51,932,669-52,012,132 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 13q14.3 | Wilson disease | 277900 | Autosomal recessive | 3 |
The ATP7B gene encodes a polypeptide that acts as a plasma membrane copper-transport protein (summary by Harris, 2000).
On YACs from the 13q14.3 region, Bull et al. (1993) identified a sequence similar to that coding for the proposed copper-binding regions of the putative ATPase gene defective in Menkes disease (MNK; 309400). They showed that this sequence forms part of a P-type ATPase gene that is very similar to MNK, with 6 putative metal-binding regions similar to those found in prokaryotic heavy metal transporters. The gene, designated ATP7B, is expressed in liver and kidney, and was found to lie within a 300-kb region likely to include the Wilson disease locus (WND; 277900). The identity between MNK and the newly identified ATP7B gene was 78% in the transduction region, 89% in the channel/phosphorylation regions, and 79% in the ATP-binding region. The predicted length of the gene product was 1,411 amino acids for ATP7B compared with 1,500 amino acids for MNK. The overall identity between the two was 57%.
Tanzi et al. (1993) used consensus DNA sequences for heavy metal binding motifs to identify homologous cDNA clones. One of these was mapped by PCR amplification and Southern blotting to contiguous YAC and cosmid clones that span the WND locus at chromosome 13q14.3. The cDNA detected a 7.5-kb RNA transcript expressed most strongly in liver and brain. Sequence analysis indicated several membrane-spanning domains, an ATPase consensus sequence, a hinge domain, a phosphorylation site, and at least 2 putative copper-binding sites. The deduced protein showed 62% amino acid homology to the Menkes disease gene.
Yang et al. (1997) stated that the full-length ATP7B protein contains 1,465 amino acids. They cloned a splice variant of ATP7B lacking exons 6, 7, 8, and 12 from a human brain cDNA library. The deduced protein contains 1,258 amino acids. Immunofluorescence localization and fractionation of a hepatoma cell line revealed that the full-length protein was associated with the Golgi apparatus and the shorter isoform was cytosolic. Full-length ATP7B did not redistribute in response to elevated copper levels, and it did not associate with the plasma membrane.
Tanzi et al. (1993) noted that the protein encoded by the ATP7B gene had the characteristics of a copper-transporting ATPase. They suggested that it may serve a function in the export of copper from cells, whereas the Menkes gene product has a role in the import of copper. Dijkstra et al. (1995) studied copper transport in rat liver plasma membranes and suggested that the ATP7B protein functions to transport copper across these membranes in the presence of ATP. Harris (2000) reviewed cellular copper transport and metabolism and stated that the ATP7B protein resides within internal compartments of the cell, where it may function to incorporate copper into apo-ceruloplasmin, and to release copper into bile.
Lim et al. (2006) stated that ATP7B localizes to the trans-Golgi network, where it transports copper to apoceruloplasmin (CP; 117700). When copper levels are in excess, ATP7B redistributes to a vesicular compartment near the biliary canalicular membranes for elimination of excess copper into bile. Using a yeast 2-hybrid screen of a human liver cDNA library, Lim et al. (2006) found that the N-terminal domain of ATP7B, which contains 6 metal-binding motifs, interacted with the C-terminal domain of the p62 dynactin subunit (DCTN4; 614758). Coimmunoprecipitation analysis revealed that ATP7B, but not ATP7A (300011), interacted with endogenous p62 in a human fibroblast line. Depletion of copper reduced interaction of ATP7B with p62. Mutation analysis revealed that the metal-binding CxxC motifs of ATP7B were required for interaction with p62, predominantly CxxC motifs 4 through 6. Lim et al. (2006) concluded that ATP7B is transported along liver cell microtubules in a copper-dependent manner via interaction with the p62 dynactin subunit.
Variant Proteins
Forbes and Cox (2000) analyzed the intracellular localization of ATP7B variant proteins using transient transfection and triple-label immunofluorescence microscopy. Two human WND ATP7B variants, asp765 to asn (606882.0012) and leu776 to val, which have normal copper transport activity in yeast, retained partial normal Golgi network localization, but were predominantly mislocalized throughout the cell and were capable of only partial copper-dependent redistribution. Variant protein arg778 to leu (R778L; 606882.0009), which has defective function in yeast, was extensively mislocalized, presumably to the endoplasmic reticulum. Variant proteins gly943 to ser (606882.0013), which has nearly normal function in yeast, and cys-pro-cys/ser (mutation of the conserved cys-pro-cys motif to ser-pro-ser), which is inactive in yeast, were localized normally but were unable to redistribute in response to copper. The authors hypothesized that mislocalization and/or deficient copper transport are defects seen in some mutant proteins, and that the nature of the malfunction(s) may explain, in part, the variable biochemical features of WND, in particular the normal holoceruloplasmin levels observed in some patients.
La Fontaine et al. (2001) generated cDNA constructs encoding the wildtype (Wnd-wt) and mutant (Wnd-tx) Wilson proteins (Wnd) and expressed them in Chinese hamster ovary (CHO) cells. The tx mutation disrupted the copper-induced relocalization of Wnd in CHO cells and abrogated Wnd-mediated copper resistance of transfected CHO cells. In addition, colocalization experiments demonstrated that while Wnd and MNK (309400) are located in the trans-Golgi network in basal copper conditions, with elevated copper, these proteins are sorted to different destinations within the same cell. Ultrastructural studies showed that with elevated copper levels, Wnd accumulated in large multivesicular structures resembling late endosomes that may represent a novel compartment for copper transport.
Luoma et al. (2010) generated yeast deficient in Ccc2, the ortholog of ATP7B, and used the Ccc2-deficient yeast model system to test the functional effect of 12 ATP7B missense variants that localize to the ATP loop of the protein. These variants may affect binding of ATP, autophosphorylation, or folding of the protein. Variants L1043P, G1000R, G1101R, I1102T, V1239G, and D1267V were found to be deleterious; G1176E and G1287S were intermediate; E1173G were temperature-sensitive; and T991M and I1148T were mild. The R1228T variant functioned similar to wildtype protein. Comparison of the functional data from the yeast model system with 3 predictive programs indicated that SIFT was most accurate (92%) followed by PolyPhen (83%) and Align-GVGD (67%).
Yang et al. (1997) determined that the ATP7B gene contains 21 exons.
Bull et al. (1993) identified the ATP7B gene in the Wilson disease critical region on chromosome 13q14.3.
Sasaki et al. (1994) identified the rat homolog of the human Wilson disease gene as the gene responsible for hepatitis (hts) in the Long Evans Cinnamon rat. They mapped the rat Wnd gene to 16q12.23-q12.3 by fluorescence in situ hybridization and mouse/rat somatic cell hybrid analysis.
Reed et al. (1995) mapped the homolog of ATP7B to mouse chromosome 8 by somatic cell hybrid analysis. Interspecific backcross analysis showed that Atp7b is close to D8Mit3 and Atp4b, another ATPase gene. Interestingly, human ATP7B occurs in a region of conserved synteny with mouse chromosome 14.
Crystal Structure
Gourdon et al. (2011) presented the structure of a P-type class IB (PIB) ATPase, a Legionella pneumophila CopA copper ATPase, in a copper-free form, as determined by x-ray crystallography at 3.2-angstrom resolution. The structure indicates a 3-stage copper transport pathway involving several conserved residues. A PIB-specific transmembrane helix kinks at a double-glycine motif displaying an amphipathic helix that lines a putative copper entry point at the intracellular interface. Comparisons to calcium ATPase suggested an ATPase-coupled copper release mechanism from the binding sites in the membrane via an extracellular exit site. Gourdon et al. (2011) suggested that their structure will provide a framework for analysis of missense mutations in human ATP7A and ATP7B proteins associated with Menkes disease and Wilson disease, respectively.
Bull et al. (1993) reported 2 patients with Wilson disease (WND; 277900) who were found to be homozygous for a 7-bp deletion within the coding region of the ATP7B gene (606882.0001). Tanzi et al. (1993) noted that a lysine-to-arginine mutation near the phosphorylation site of the ATPase occurred in 85% of all WND chromosomes analyzed and in only 15% of 'normal' chromosomes in diverse populations. Tanzi et al. (1993) identified 4 mutations in unrelated persons with Wilson disease: 2 missense mutations and 2 frameshift mutations resulting in a truncated gene product (606882.0002-606882.0005). The mutations were found among 50 unrelated families derived predominantly from the United States, 18 unrelated families from Russia, and 5 presumably unrelated families from Sicily. Clearly, Bull et al. (1993) and Tanzi et al. (1993) had independently isolated the same gene which was convincingly the one mutant in Wilson disease.
Thomas et al. (1995) reviewed the mutations found in the ATP7B gene. In 58 patients with Wilson disease, they found 20 new mutations as well as 3 of the 5 previously published mutations: 11 small insertions and deletions, 7 missense mutations, 2 nonsense mutations, and 3 splice site mutations. Two of the mutations, his1070 to gly (606882.0006) and gly1267 to arg (606882.0007), are relatively frequent, together accounting for 38% of mutations in patients of European origin. Their findings suggested a wide span in the age of onset of Wilson disease, perhaps wider than previously considered typical. Mutations that completely disrupt the gene can produce liver disease in early childhood at a time when Wilson disease may not be considered in the differential diagnosis.
Given the difficulties of searching for mutations in a gene spanning more than 80 kb of genomic DNA, haplotype data are important as a guide to mutation detection. Thomas et al. (1995) did haplotyping of the Wilson disease gene region in 58 families. These haplotypes, combining 3 markers (D13S314, D13S316, and D13S301), were usually specific for each different mutation. The haplotype data suggested that as many as 20 mutations might still be unidentified; a total of 25 disease-causing mutations had been identified at that time.
Figus et al. (1995) identified 16 novel mutations in 127 affected patients of Mediterranean descent: 8 frameshifts, 7 missense mutations, and 1 splicing defect. In addition, they detected 5 previously described mutations, e.g., his1070-to-gln (606882.0006), which accounted for 13% of the mutations in WND chromosomes in non-Sardinian Mediterranean populations.
Loudianos et al. (1999) characterized the putative promoter and 5-prime untranslated region of the WD gene and carried out mutation analysis in this region in Sardinian WD patients with the most common haplotype. They detected a single mutation resulting from a 15-nucleotide deletion (606882.0010) in all chromosomes with this common haplotype. With the addition of this mutation, the molecular defect has been found in 92% of the WD chromosomes in Sardinians.
Loudianos et al. (1998) performed a mutation screen on the WND gene in 59 patients of Mediterranean origin: 26 Continental Italians, 22 Sardinians, 9 Turkish, and 2 Albanians. They found 31 novel and 3 known mutations. Most of the patients were compound heterozygotes.
Kim et al. (1998) identified 3 novel mutations in the ATP7B gene in Korean patients with Wilson disease. One of these, arg778 to leu (R778L; 606882.0009), was found in 6 of 8 unrelated patients, giving an allele frequency of 37.5%.
Duc et al. (1998) performed mutation analysis in 33 German and 10 Cuban unrelated Wilson disease patients. The common his1069-to-gln (606882.0006) mutation accounted for 42% of all WND chromosomes in the German series and haplotype C was found to be highly predictive for this mutation. Six previously undescribed WND gene mutations were identified. In 15 German WND index patients and 3 sibs, both WND mutations could be determined and a genotype-phenotype correlation was attempted. Patients homozygous for the his1069-to-gln mutation showed almost a complete range of clinical presentations; thus, in this study, the his1069-to-gln mutation was not associated with a late neurologic presentation.
Okada et al. (2000) analyzed the ATP7B gene in 41 unrelated Japanese Wilson disease families, including 47 patients. They identified 21 mutations, 9 of which were novel.
In 84 Chinese patients with Wilson disease from 65 unrelated families, Wu et al. (2001) identified 18 mutations (7 novel) and 11 polymorphisms (3 novel) in the ATB7B gene. The most common mutations were R778L and T935M, which were present at a frequency of 37.7% and 10.0%, respectively.
Loudianos et al. (2002) stated that more than 200 Wilson disease-causing mutations had been defined, most of which were missense mutations, while splice site mutations were limited in number.
Yoo (2002) studied 37 patients from 33 unrelated Korean families with Wilson disease and identified 12 different mutations, of which 6 were novel. The R778L mutation, which is known to be highly prevalent in Asian patients, was found with a frequency of 37.9% among the Korean population, which is significantly higher than that among the Japanese and Taiwanese. The N1270S mutation (606682.0017), which is presumed to disrupt the ATP hinge domain of the ATP7B protein, was the next most common mutation in Korean patients, with an allele frequency of 12.1%. The A874V mutation (606682.0016) was the third most common, accounting for 9.4%.
Panagiotakaki et al. (2004) analyzed the results of molecular analysis on a cohort that included 93 index patients with Wilson disease from 69 unrelated families in Greece. Detailed phenotypic evaluation was added to the findings reported previously by Loudianos et al. (1998, 2000). Twenty different mutations accounted for 86% of the WND chromosomes. The 2 most common mutations were H1069Q (606882.0006), found in 35% of WND chromosomes, and R969Q (606882.0018), found in 12%. Homozygosity for H1069Q was found in 13 patients and for R969Q in 7.
Margarit et al. (2005) analyzed 40 unrelated Spanish patients with Wilson disease and identified 21 different mutations in the ATP7B gene in 35 (87%) patients. The M645R (606882.0020) mutation was particularly prevalent and was found in 22 patients (55%), who were all compound heterozygotes for mutation in the ATP7B gene.
Dedoussis et al. (2005) observed an increased number of WD patients on the island of Crete and studied the spectrum of mutations in a small village close to the city of Heraklion. Of 90 births in the village since 1978, 6 were found to have WD. Analysis of the entire gene in 3 WD patients and in relatives of a boy who died from WD led to the detection of 4 different mutations. Two missense mutations (see 606882.0021) cosegregated in cis in the same patient. The other allele of this patient carried a nonsense mutation (606882.0022). This was said to have been the first report of 3 mutations cosegregating in the same WD patient. The fourth mutation identified was a novel frameshift mutation with documented cosegregation with WD. A screen of 200 inhabitants originating from the same area demonstrated that 18 were carriers of one of these mutations.
Gupta et al. (2005) analyzed Indian patients with Wilson disease from 62 unrelated families and their first-degree relatives and identified a total of 9 mutations, 5 novel, in the ATP7B gene. The authors noted that homozygotes for different mutations that would be expected to produce similar defective proteins showed significant disparity in terms of organ involvement and severity of disease; in 1 family, 2 sibs with the same pair of mutant chromosomes had remarkably different phenotypes. Gupta et al. (2005) suggested that there may be as yet unidentified modifying loci that account for the observed phenotypic heterogeneity among patients with Wilson disease.
In 120 unrelated Korean patients with Wilson disease, Park et al. (2007) identified 28 different mutations, including 6 novel mutations, in the ATP7B gene. R778L was the most common mutation, occurring in 39.2% of mutant alleles. Functional studies of some of the mutant proteins in yeast cells and COS-7 cells showed impaired copper transport and aberrant cellular localization of mutant ATP7B proteins.
Wallace and Dooley (2020) found that of the 732 Wilson disease-associated ATP7B mutations reported by 2017, most (55%) were missense mutations. Of the 732 mutations, 231 were present in the gnomAD database, giving an initial estimated population prevalence of 1 in 2,400. Wallace and Dooley (2020) assessed the penetrance/pathogenicity of ATP7B mutations by comparing gnomAD allele frequencies with the number of reports of each mutation and then using a variant effect prediction algorithm. When the authors reassessed the pathogenic allele frequency of ATP7B mutations excluding those likely to have low penetrance, they calculated the population prevalence of Wilson disease to be 1 in 20,000 individuals.
Panagiotakaki et al. (2004) studied a Wilson disease cohort that included 93 Greek index patients from 69 unrelated families and reported that the H1069Q and R969Q mutations appeared to confer a milder disease as patients showed disease onset at a later age and also were associated with milder severity when found in trans (compound heterozygosity) with severe mutations. Predicted nonsense and frameshift mutations were associated with severe phenotypic expression with earlier disease onset and lower ceruloplasmin values. Panagiotakaki et al. (2004) noted that their findings on the phenotypic effect of predicted nonsense and frameshift mutations were especially important for early medical intervention in presymptomatic infants and children with these genotypes.
Gromadzka et al. (2005) studied 142 Polish patients with Wilson disease and identified 26 mutations in the ATP7B gene: 11 truncating, 14 missense, and 1 splice site mutation. Patients with 1 or 2 truncating mutations had lower serum copper and ceruloplasmin levels and were younger when the first symptoms of the disease appeared compared with individuals with 2 missense mutations, and the effect of truncating mutations on phenotype was dose-dependent. Gromadzka et al. (2005) found no association between type of ATP7B mutation and mode of initial disease presentation (neurologic, hepatic, or mixed).
Terada et al. (1998) introduced human ATP7B cDNA into the LEC rat using recombinant adenovirus-mediated gene delivery. An immunofluorescence study and a subcellular fractionation study revealed the transgene expression in liver and its localization to the Golgi apparatus. Moreover, since the synthesis of holoceruloplasmin is disturbed in the LEC rat, the plasma level of holoceruloplasmin, oxidase-active and copper-bound form, was examined to evaluate the function of ATP7B protein with respect to copper transport. Holoceruloplasmin was found in plasma of LEC rats who received ATP7B cDNA. Terada et al. (1998) concluded that introduced ATP7B protein may function in the copper transport coupled with the synthesis of ceruloplasmin and that the Golgi apparatus is the likely site for ATP7B protein to manifest its function.
To confirm the conclusion that the gene they identified in a YAC from the 13q14.3 region and referred to as Wc1 was indeed the gene mutated in Wilson disease (WND; 277900), Bull et al. (1993) studied 30 patients with the disorder selected to represent 29 different haplotypes based on 3 close markers. Using 3 cDNA fragments and 3 restriction enzymes, they found no altered fragments or dosage differences indicative of gross deletions. Single-strand conformation polymorphism analysis and heteroduplex analysis were performed in 27 patients. Both methods revealed a particular band shift, which on sequencing was found to represent homozygosity for the same 7-bp deletion, removing bases 1950-1956 of their sequence, causing a frameshift that resulted in an immediate stop codon at position 639 in the amino acid sequence, and removing the entire C-terminal half of the protein.
The name of the 7-bp deletion (1950del7), originally described by Bull et al. (1993), was changed to 2010del7 to be consistent with the position of the ATG start codon identified by Petrukhin et al. (1994). The same mutation was found by Thomas et al. (1995) in affected members of 2 large kindreds in Iceland. Haplotype data and the nature of the mutation supported the existence of a founder chromosome. Although the protein function was predicted to be completely abolished by the deletion, predicting early-onset liver disease, Thomas et al. (1995) found that the patients presented with later-onset neurologic and psychiatric symptoms. They showed that alternative splicing of the transcript in the region of the deletion may have contributed to later onset, suggesting that alternative isoforms of the protein may have functional significance.
In 31% of Wilson disease (WND; 277900) chromosomes in 50 unrelated Americans and in 22% of Wilson disease chromosomes in 18 unrelated Russian families, Tanzi et al. (1993) found a C-to-A transversion at nucleotide 2142 in the ATP7B gene, causing a substitution of glutamine for histidine-714 in the phosphorylation domain of the protein. Houwen et al. (1995) analyzed 38 Dutch symptomatic Wilson disease patients for the H714Q mutation. Ten patients homozygous for the mutation presented at a mean age of 20.3 (SD 6.1) years, with either neurologic symptoms or a Kayser-Fleischer ring. Six patients with the H714Q mutation in one chromosome and an unknown mutation in the other chromosome presented at a mean age of 17.8 (SD 5.8) years, with either neurologic or hepatic symptoms. With the exception of 1, all 22 patients with an uncharacterized mutation in both chromosomes presented with liver involvement at a mean age of 9.9 (SD 2.4) years. The findings suggest that the H714Q mutation is a relatively mild one, possibly with some residual function in the copper transporting protein, resulting in a slower build-up of copper.
In a Sicilian case of Wilson disease (WND; 277900), Tanzi et al. (1993) found an A-to-G transition at nucleotide 2744, resulting in substitution of serine for asparagine-915 in the hinge region of the ATP-binding site. This region is highly conserved in all P-type ATPases. The Sicilian patient was homozygous for the mutation and was also homozygous for a 6-marker haplotype that had not been observed in other individuals in their sample of 115 Wilson disease families. Thus, it appears to be a rare mutation.
In 2 Russian patients with Wilson disease (WND; 277900), Tanzi et al. (1993) found homozygosity for a single basepair deletion, a cytosine at position 2337. This resulted in a frameshift at amino acid 779. In both families, the parents were heterozygous for the mutation, as was a single unaffected sib. The mutation accounted for approximately 20% of Wilson disease chromosomes in a sample of 18 unrelated Russian families. It was found once in an American sample of 50 unrelated families. It was predicted that the mutation would truncate the Wilson disease protein within the phosphorylation region, thereby disabling its function in persons homozygous for the mutation.
On 1 chromosome of an American patient with Wilson disease (WND; 277900), Tanzi et al. (1993) found insertion of an extra thymine residue after thymine 2487, resulting in a frameshift at amino acid 829. The change in the protein was in the amphiphilic helix between the phosphorylation and ATP-binding domains. The second disease allele in this patient had not been identified.
In a study of 58 patients with Wilson disease (WND; 277900), Thomas et al. (1995) found that 28% had a mutation that they referred to as H1070Q (HIS1070GLN), located in the loop motif and disrupting ATP binding. The patients (19 in number) were of Eastern European, German, French, and British extraction. This mutation was homozygous in 6 families; there was variation in age of onset within these families and an equal number of hepatic and neurologic cases. The average age of onset of symptoms in patients homozygous for the mutation was 16.8 years. The same mutation was found in heterozygous state (compound heterozygotes) in 9 families with a total of 11 patients, with an average age of onset of 17.3 years. Figus et al. (1995) concluded that this mutation is probably the most common molecular defect of the WND gene and may have arisen as a single and very ancient mutation event.
Payne et al. (1998) stated that the H1069Q mutation represents up to 37% of Wilson disease alleles in patients of Eastern European descent and studied the function of the ATP7B protein by expressing wildtype and mutant ATP7B cDNAs in a Menkes copper transporter-deficient 'mottled' fibroblast cell line defective in copper export. Expression of the wildtype cDNA demonstrated trans-Golgi network localization and copper-dependent trafficking of the ATP7B protein identical to previous observations for the endogenously expressed protein in hepatocytes. Furthermore, expression of the ATP7B cDNA rescued the 'mottled' phenotype as evidenced by a reduction in copper accumulation and restoration of cell liability. In contrast, expression of an H1069Q mutant ATP7B cDNA did not rescue the 'mottled' phenotype, and immunofluorescence studies showed that this mutant ATP7B protein was localized in the endoplasmic reticulum. Pulse-chase analysis demonstrated a 5-fold decrease in the half-life of the H1069Q mutant as compared with the wildtype protein. Maintenance of these transfected cell lines at 28 degrees C resulted in localization of the H1069Q protein in the trans-Golgi network, suggesting that a temperature-sensitive defect in protein folding followed by degradation constitutes the molecular basis of Wilson disease in patients harboring the H1069Q mutation. The results provided compelling evidence that the ATP7B protein can functionally substitute for the Menkes disease protein, ATP7A, supporting the concept that these proteins use common biochemical mechanisms to effect cellular copper homeostasis.
Duc et al. (1998) found this mutation in 42% of WND chromosomes in a series of 33 German cases of Wilson disease. Haplotype C was highly predictive for this mutation. Patients homozygous for the mutation showed almost a complete range of clinical presentations; in this series, the his1069-to-gln mutation was not associated with a late neurologic presentation.
Firneisz et al. (2002) found the H1069Q mutation in 27 Hungarian patients with Wilson disease, 64.3% of their series. In 9 of the 27 patients, H1069Q was homozygous. They found that H1069Q-positive patients from various European countries had the same haplotype pattern. Thus the H1069Q mutation appears to have originated from a single founder, at least in Europe.
Among 80 unrelated Bulgarian families with Wilson disease, Todorov et al. (2005) found that the H1069Q mutation was the most common mutation with an allelic frequency of 58.75%. All 15 families of the Roma ethnic group had the H1069Q mutation, consistent with the Roma being a genetic isolate with frequent consanguinity and endogamy.
In a series of 58 patients with Wilson disease (WND; 277900), Thomas et al. (1995) found that 7 (10%), of French and British extraction, had a gly1267-to-arg mutation. Located in the ATP hinge domain, the mutation disrupted the hinge. (The article by Thomas et al. (1995) listed this mutation as GLY1267LYS; a published correction provided the proper amino acid substitution.)
In a series of 58 patients with Wilson disease (WND; 277900), Thomas et al. (1995) found 4 with mutations predicted to destroy the function of the gene (insertion, deletion, nonsense, or frameshift). The average age of onset in these cases was 7 years. Most striking was the age of onset of a patient homozygous for a G-to-C transversion at nucleotide 1711. The patient, of American Indian extraction, presented with liver disease at 3 years of age. The mutation at the acceptor splice site of intron 4 resulted in the deletion of exon 5 and the removal of 54 amino acids, including the last copper-binding domain, from the protein product.
Wilson et al. (2000) reported a 3-year-old Indo-Pakistani girl, born to consanguineous parents, who was diagnosed with Wilson disease after presenting with hemolytic anemia, hepatosplenomegaly, ascites, and evidence of decompensated chronic liver disease. DNA analysis revealed that she was homozygous for the IVS4-1G-C mutation.
Kim et al. (1998) found a CGG-to-CTG transversion in exon 8 of the ATP7B gene, leading to an arg778-to-leu (R778L) amino acid substitution in 6 of 8 unrelated Korean patients with Wilson disease (WND; 277900). They cited the allele frequency as 37.5% and quoted previous findings indicating a considerable frequency of this allele in Japanese (27.7%), Taiwanese (27%), and Chinese (11.1%) Wilson disease patients.
Kusuda et al. (2000) described the R788L mutation in compound heterozygous state with an in-frame deletion, 3892delGTC (606882.0011), in a Japanese patient. Likewise, they commented on the high frequency of this mutation in Asians and stated that it has not been reported in Caucasian patients.
Wu et al. (2001) reported the frequency of the R788L mutation in Chinese patients to be 37.7%, which represented the most common mutation found in 84 patients with Wilson disease. The authors also found that homozygosity for the mutation was associated with a significantly earlier age of disease onset, lower levels of ceruloplasmin, and hepatic symptoms at presentation as compared to heterozygosity.
Gu et al. (2003) likewise found the R778L mutation in 55% of Chinese Han and Hui patients in at least 1 allele.
Park et al. (2007) found that the R778L mutation had an allele frequency of 39.2% among 120 unrelated Korean patients with Wilson disease.
Park et al. (2009) found heterozygosity for the R778L allele in 6 of 500 healthy Korean individuals, yielding a carrier frequency of 0.6% in this population.
Wang et al. (2011) found that the R778L mutation was the most common mutation among 69 Chinese patients with Wilson disease, accounting for 23.29% of mutant alleles.
Loudianos et al. (1999) characterized the putative promoter and 5-prime untranslated region of the WND gene and carried out mutation analysis in this region in Sardinian patients with Wilson disease (WND; 277900) with the most common haplotype. They detected a single mutation resulting from a 15-nucleotide deletion from position -441 to position -427, 5-prime to the translation start site within the 5-prime UTR in all chromosomes with this common haplotype. Expression assays demonstrated a 75% reduction in the transcriptional activity of the mutated sequence compared to that of the normal sequence. With the addition of this mutation, the molecular defect has been found in 92% of the WD chromosomes in Sardinians.
Cullen et al. (2003) examined genetic variation in the promoter and 5-prime UTR of the ATP7B gene in patients with Wilson disease. Three of 37 patients were heterozygous for the 15-bp deletion between nucleotides -424 and -441. In addition, 2 novel single-nucleotide changes were identified within the 5-prime UTR and promoter of ATP7B, but these were found at a similar frequency in control chromosomes and were apparently normal variants. The results suggested that mutations in regulatory elements of ATP7B are uncommon in patients of European ancestry, except in Sardinia.
In a Japanese patient with Wilson disease (WND; 277900), Kusuda et al. (2000) found compound heterozygosity for an in-frame GTC deletion (3892delGTC), predicted to remove a valine residue, and the frequent Asian mutation R778L (606882.0009), which apparently has not been observed in Caucasians.
In patients with Wilson disease (WND; 277900), Figus et al. (1995) identified a GAC-to-AAC change in the ATP7B gene, resulting in an asp765-to-asn substitution.
In patients with Wilson disease (WND; 277900), Thomas et al. (1995) identified a GGT-to-AGT change in the ATP7B gene, resulting in a gly943-to-ser mutation.
In 3 sibs with disparate clinical phenotypes of Wilson disease (WND; 277900), Takeshita et al. (2002) found compound heterozygosity for 2 ATP7B mutations: R778L (606882.0009) and R919G.
In a family in which 2 sibs had disparate Wilson disease (WND; 277900) phenotypes, Takeshita et al. (2002) found that each had compound heterozygosity for 2 ATP7B mutations: 2511delA and A874V (606882.0016). In this family, the second male child showed neurologic symptoms at 32 years of age and was found to have the hepatoneurologic type of Wilson disease; on subsequent family screening, the 35-year-old first female sib was found to have the hepatic form.
For discussion of the ala874-to-val (A874V) mutation in the ATP7B gene that was found in compound heterozygous state in 2 sibs with Wilson disease (WND; 277900) by Takeshita et al. (2002), see 606882.0015.
Park et al. (2009) found heterozygosity for the A874V allele in 2 of 500 healthy Korean individuals, yielding a carrier frequency of 0.2% in this population.
Thomas et al. (1995) identified an asn1270-to-ser (N1270S) mutation, which they referred to as asn1271-to-ser (N1271S), in the ATP7B gene in an Italian patient with Wilson disease (WND; 277900). This mutation was found to account for 61% of all mutations in Costa Rican patients and 4.9% in Japanese patients (Okada et al., 2000; Shah et al., 1997). Yoo (2002) found this mutation in 12.1% of Korean patients with Wilson disease. In most cases it was found in compound heterozygosity with the R778L mutation (606882.0009).
Park et al. (2009) found heterozygosity for the N1270S allele in 2 of 500 healthy Korean individuals, yielding a carrier frequency of 0.2% in this population.
In patients with Wilson disease (WND; 277900), Figus et al. (1995) identified a 2906G-A transition in exon 13 of the ATP7B gene, resulting in an arg969-to-gln (R969Q) substitution. Panagiotakaki et al. (2004) found this mutation in 12% of chromosomes from 93 Greek patients with Wilson disease.
In a patient with Wilson disease (WND; 277900), Pendlebury et al. (2004) identified a homozygous thr766-to-arg (T766R) substitution in the ATP7B gene within transmembrane domain 4 of the protein. The case was unusual in that the patient presented with sudden onset of slurred speech, dysphagia, and difficulty walking. A preliminary diagnosis of ischemic stroke was made, but a more detailed work-up suggested Wilson disease. Both parents were heterozygous for the mutation and originated from the same small village in central England.
In 22 of 40 (55%) unrelated Spanish patients with Wilson disease (WND; 277900), Margarit et al. (2005) identified a met645-to-arg (M645R) substitution in exon 6 of the ATP7B gene, between the sixth copper-binding domain and the first transmembrane region. The patients were all compound heterozygotes for mutation in the ATP7B gene, and all had the hepatic form of the disease. In 6 patients in whom M645R was combined with a nonsense mutation, there was early onset of the disease, occurring between 5 and 14 years of age.
In a patient with Wilson disease (WND; 277900) from a small village in Crete with an unusually high frequency of the disorder, Dedoussis et al. (2005) identified compound heterozygosity involving 3 different mutations in the ATP7B gene. An ile1148-to-thr substitution (I1148T) and a gly1176-to-arg substitution (G1176R) cosegregated in cis in the same patient. The other allele of this patient carried a nonsense mutation (Q289X; 606882.0022).
For discussion of the gln289-to-ter (Q289X) mutation in the ATP7B gene that was found in compound heterozygous state in a patient with Wilson disease (WND; 277900) by Dedoussis et al. (2005), see 606882.0021.
In 18 individuals with Wilson disease (WND; 277900) from the Canary Islands of Spain, Garcia-Villarreal et al. (2000) identified a T-to-C transition in exon 8 of the ATP7B gene, resulting in a leu708-to-pro (L708P) substitution. Twelve patients were homozygous for the mutation. Homozygous patients tended to have a neurologic presentation at an average age of 16 years. Haplotype analysis indicated a founder effect. The L708P mutation was estimated to have arisen in Gran Canaria over 56 generations ago, in pre-Hispanic times.
In 5 affected members of a consanguineous Lebanese family with Wilson disease (WND; 277900), Barada et al. (2007) identified a homozygous G-to-A transition in exon 7 of the ATP7B gene, resulting in a gly691-to-arg (G691R) substitution in the TM2 domain. Four SNPs in the ATP7B gene were also inherited homozygously with the G691R substitution and may have contributed to altered protein function. Two patients presented at ages 7 and 9 years, respectively, with advanced hepatic cirrhosis. The 3 other affected individuals, who were asymptomatic, were detected by screening before age 14. Four additional family members, 3 of whom were deceased, were reportedly affected.
In Chinese patients with Wilson disease (WND; 277900), Wang et al. (2011) identified a 3443T-C transition in exon 16 of the ATP7B gene, resulting in an ile1148-to-thr (I1148T) substitution in the ATP loop of the protein. The I1148T mutation was the second most common mutation among 69 Chinese patients with Wilson disease, accounting for 9.59% of mutant alleles.
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