English abstract
Wilson's disease (WD, Hepatolenticular degeneration) is an inherited autosomal recessive disorder of copper transport. It is characterised by impaired biliary excretion and deficient incorporation of copper into ceruloplasmin. This leads to toxic accumulation of copper in the liver and subsequent overflow and accumulation in the brain, kidney, and cornea. Thus, excess accumulation of copper can cause tissue damage leading to hepatic, neurological, and psychiatric disturbances, or combinations of the three. Patients with liver disease generally present in childhood or adolescence. Neurological and psychiatric symptoms begin at older ages. WD occurs in populations of every geographical and ethnic origin. The worldwide prevalence of WD is estimated to be 1:30 000, with a corresponding gene frequency of 0.56% and a carrier frequency of about 1/90. ATP7B, the gene mutated in WD, has 21 exons and encodes a protein of 1465 amino acids. The protein is a copper transporting P-type ATPase. To date, more than 200 mutations have been detected in the ATP7B gene, few of which are common to several populations, with most being population specific. We detected in Omani patients with WD a novel substitution mutation, IV$13-2A>G, in exon 13 of the ATP7B gene.
Two Omani families with index Wilson Disease individuals were included in this study. They were from Dhofari (S) and Balushi (B) families. Dhofari family had two affected siblings who were in different stages of the disease. The older was suffering from neurological problems while his younger brother has hepatic manifestations. The Balushi family is a big pedigree with many consanguineous marriages. Three Balushi nuclear families were studied with a total number of eight affected siblings. DNA was collected from 76 individuals. The ATP7B gene was sequenced in many affected and non affected individuals. A total of 16 SNPs were identified from both families. The SNPs sets were different in the two families. This confirmed that the two families were of different ethnic origins. Results have further been supported by the Haplotyping analysis which estimated one haplotype block with three haplotype tagging SNPs (htSNPs). A possible disease-causing mutation (IVS13-2A>G) was detected in the Balushi family. However, this mutation was not detected in the Dhofari family. Mutation of IVS13-2A>G is located at the splicing site of exon-13 which encodes the phosphatase domain of ATPase functional region. It reported previously in the NCBI/SNP database, the Wilson Disease database or any other publication. Therefore, this seems to be a novel mutation that may explain WD in the Balushi family. Yet the definitive proof awaits functional studies. Detection of this mutation in the Balushi family and not in the Dhofari family supports the idea that WD in Oman is genetically heterogeneous. The family pedigree constructed for the two families will prove useful later for genetic counselling..
