2. Biochemistry, molecular biology and molecular genetics of Wilson disease

Wilson disease (WD) (hepatolenticular degeneration) is an autosomal recessive disorder of copper metabolism due to absence or dysfunction of a Cu P-type ATPase which is essential for the transport of copper (Cu) into the bile. The discovery of the gene cation transporting P-type ATPase involved in the copper transport in many tissues was a breakthrough in the understanding of molecular basis of the defect of Cu metabolism in Wilson disease (WD). The Wilson disease occurs as a result of the defect in the gene, designated as ATP7B, which encodes a Cu transporting P-type ATPase. WD occurs worldwide with an average prevalence of ~30 individuals/million. It is characterized by excessive copper deposition, predominantly in the liver and brain. Diagnosis of WD is based on various clinical and biochemical parameters and the presence of the Kayser-Fleischer ring. Wilson disease is caused by various mutations within the ATP7B gene. Among the ethnic groups tested so far, some have predominantly distinct mutations. The p.H1069Q mutation is detectable in 60% of disease causing alleles in central Europe. Another common mutation p.R778L is detectable in 45% of WD population in China, whereas the c.3402delC mutation is present in 30% of WD population in Brazil. Therefore, depending on the ethnic background, distinct mutations can be first screened. However, Correspondence/Reprint request: Prof. Rajendra Prasad, Department of Biochemistry, Post Graduate Institute of Medical Education and Research, Chandigarh -160012, India. E-mail: [email protected] Rajendra Prasad & Sandeep Kumar 26 subsequent genetic analysis remains demanding because >800 mutations within ATP7B gene have been already detected, and most are in compound heterozygous state in WD patients. In 2005, first time ever our lab has characterized 22 mutations comprising 14 insertion/deletion, five missense, two splice sites, and one nonsense mutation suggesting that exons 8, 12, 13, 15, 16, and 18 of ATP7B are hot spots for mutations in Indian WD patients. Currently, based on available reports from different parts of India C813A, C271X, C27I, E122fs, R778W, I1102T, c.3182G>A are the most common mutations in Indian WD patients. Unfortunately, there is no single predominant mutation noted in the Indian WD population unlike other countries, thus suggesting genetic and ethnic heterogeneity in India. The treatment of WD based on chelation of copper ions with drugs such as D-penicillamine is not considered as a good approach due to the reported side effects. Contrary to this, agents such as trientine and ammonium tetrathiomolybdate have shown promising effects but still the results of the long term trials are awaited. In some cases, it was observed that orthotropic hepatic transplantation can rescue the basic metabolic aberrations as well as show improvements in both hepatic and neurological symptoms. Better understanding of the defect in ATP7B gene and its associated modifier genes may lead to the designing of the strategies to develop new therapies for prevention and treatment of Wilson disease.