Molecular characterization of Wilson disease in the Sardinian population -Evidence of a founder effect

Wilson disease (TI;VD) in the Sardinian population has an approximate incid ence of 1:7,000 live births, Mutation analysis of the WD gene in this popul ation reported in our previous articles led us to the characterization of t wo common mutations and a group of 13 rare mutations accounting for the mol ecular defect of 8.5, 7.9, and 15.1% of the WD chromosomes. However, molecu lar analysis of the WD chromosomes containing the most common haplotype, wh ich accounts for 60.5% of the WD chromosomes, failed to define the disease- causing mutation. In this study, we characterized thc:promoter and the 5' U TR of the WD gene sequence and carried out a mutation analysis in this DNA region from patients with the most common haplotype, The promoter is contai ned in a GC-rich island and shows a TATA and a CAAT consensus sequence as w ell as potential binding sires for transcription factors and metal response elements. In all the analyzed 92 chromosomes with this haplotype, we detec ted a single mutation consisting of a 15-nt deletion from position -441 to position -427 relative to the translation start site. Expression assays dem onstrated a 75% reduction in the transcriptional activity of the mutated se quence compared to the normal control. By adding this mutation to those tha t have been already characterized, we have now defined the molecular defect in 92% of the WD chromosomes in Sardinians, The high frequency, the expect ed prevention by preclinical diagnosis and early treatment of the devastati ng effect: of WD on the nervous system and liver tissue, and the feasibilit y to detect most: of molecular defects by DNA analysis indicate that WD in the Sardinian population should be added to the list of diseases currently detected by newborn screening. Hum Mutat 14:294-303, 1999. (C) 1999 Wiley-L iss, Inc.