Novel mutations of ATP7B gene in Wilson's disease patients of South Indian cohort

Wilson Disease is an autosomal recessive inherited disorder caused by abnormal copper metabolism. Mutations in P-type adenosine triphosphatase -ATP7B gene are known to result in excessive copper deposition in liver, brain and cornea leading to hepatic, and neuropsychiatric manifestations. Wide clinical and genetic heterogeneity is observed despite being a monogenic condition, making diagnosis difficult. Unlike other populations where a common causal mutation has been established, Indian population has revealed heterogeneous data attributing to its genetic diversity. Therefore we considered screening of ATP7B gene to identify any novel disease causing mutation and establish genotype-phenotype correlation.Genetic screening of the entire coding region of ATP7B gene was carried out in thirteen WD patients and nine of available family members by PCR based direct sequencing for hotspot exons 8, 13, 14, 15 and 18 and PCR based SSCP analysis for the rest of 16 exons.We report five novel mutations (3 missense, 1 frameshift and 1 intronic) and five reported mutations (2 missense, 1 silent, 1 intronic and 1 in 5′UTR). Mutations were mostly observed in hotspot exons 8, 13 and 18. Genotype-phenotype correlation revealed predominance of mutations in certain clinical subtype along with regional variation. Molecular genetic analysis has proved to be the most reliable method for confirmation of clinical diagnosis and identification of pre-symptomatic individuals, however screening of the entire gene can be time consuming and an expensive method. Since the hotspot exons: 8, 13, 14, 15, and 18 constitute for nearly 85% of the mutations, screening of these exons can be an efficient and an economical option.