RNA analysis of consensus sequence splicing mutations: implications for the diagnosis of Wilson disease.

Wilson disease (WD) is an autosomal recessive disorder caused by a defective function of the copper-transporting ATP7B protein. This results in progressive copper overload and consequent liver, brain, and kidney damage. Approximately 300 WD-causing mutations have been described to date. Missense mutations are largely prevalent, while splice-site mutations are rarer. Of these, only a minority are detected in splicing consensus sequences. Further, few splicing mutations have been studied at the RNA level. In this study we report the RNA molecular characterization of three consensus splice-site mutations identified by DNA analysis in WD patients. One of them, c.51 + 4 A → T, resides in the consensus sequence of the donor splice site of intron 1; the second, c. 2121 + 3 A → G, occurred in position + 3 of intron 7; and the c.2447 + 5 G → A is localized in the consensus sequence of the donor splice site of intron 9. Analysis revealed predominantly abnormal splicing in the samples carrying mutations compared to ...