Wilson's Disease: An Update

Shyamal K Das; Kunal Ray


Nat Clin Pract Neurol. 2006;2(9):482-493. 

In This Article

Epidemiology and Molecular Biology

WD is caused by mutations to the gene coding for ATPase copper transporting beta polypeptide (ATP7B), which is located on chromosome 13[5,6,7,8] and is expressed predominantly in the liver. The disease is inherited in an autosomal recessive manner. WD is present in most populations worldwide, and particularly in those in which consanguineous marriage is common. The disease frequency is estimated to be between 1 in 5,000 and 1 in 30,000, and the carrier frequency is approximately 1 in 90.[9] A variety of defects have been identified in the ATP7B gene of WD patients, the majority of which are located in the transmembrane region of the associated protein. These defects include insertion, deletion, splice site and point mutations. Many of the mutations identified are described in various databases.[10,11] In most ethnic groups, either one or a small number of these ATP7B mutations are prevalent, in addition to many other more rare mutations. For instance, among Europeans and North Americans, two ATP7B point mutations—His1069→Gln and Gly1267→Arg—together account for 38% of the observed mutations in WD.[12] A 15-nucleotide deletion underlying the most common haplotype seen in Sardinians has been reported,[6] as has a missense mutation (Arg778→Leu) found among Mongoloids.[13] Recently in India, seven recurring haplotypes were identified that account for 58% of the different mutant chromosomes in WD, and four underlying defects in ATP7B representing 37% of WD chromosomes were also detected.[14]ATP7B is a relatively large gene at around 80 kb, and it contains 21 exons.[15] Knowledge of the prevalent mutations is therefore of help in achieving rapid mutational screening.

The molecular basis for the observed phenotypic variation in patients with similar mutations to the ATP7B gene is not clear, but might result from environmental factors that include variability in nutritional copper intake. Modifier genes such as COMMD1 (also known as MURR1)—the gene responsible for canine WD—and ATOX1 might have a role in the sensing or trafficking function of the WD protein, and in patients with the apolipoprotein E ε3/3 genotype the onset of symptoms is sometimes delayed.[16] Compound heterozygotes for the ATP7B mutation are frequent in WD, which makes the genotype-phenotype correlation challenging. Frame shift deletions and nonsense mutations that cause a truncation of the translated protein product usually result in a severe form of the disease because of loss of the functional protein.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.