title: Late neurological presentations of Wilson disease patients in French population and identification of 8 novel mutations in the ATP7B gene.
abstract: Wilson disease (WD) is an autosomal recessive disorder of copper biliary excretion caused by an impaired function of ATP7B, a metal-transporting P-type ATPase encoded by WD gene. It results in copper accumulation, mostly in liver and brain tissues. Mutation analysis was carried out on 11 WD French unrelated patients presenting a predominant neurological form of this illness. SSCP and dHPLC analysis followed by sequencing of the 21 exons and their flanking introns were performed. Thirteen different mutations in a total of 17, and, among them, 10 novel variants were evidenced. Two deletions (c.654_655delCC and c.1745_1746delTA), 4 missense mutations (p.F763Y, p.G843R, p.D918A and p.L979Q), 1 nonsense mutation (p.Q1200X), 1 splice site mutation (c.1947-1G>C) and 2 intronic silent substitutions (c.2448-25G>T and c.3412+13T>A) were detected. These data extend the mutational spectrum of the disease, already known to be a very heterogeneous genetic disorder. As compared to hepatic manifestations, the phenotypes associated to these mutations confirm that neurological presentations associated with other mutations than p.H1069Q are also often late in their onset. Most of these neurological forms probably correspond to an attenuated impairment of copper metabolism, as compared to hepatic forms of the disease, mostly diagnosed earlier.
authors.affiliation: Hôpital Lariboisière, Centre National Référence Bernard Pépin pour la Maladie de Wilson, Service de Biochimie et Biologie Moléculaire, 2, rue A. Paré, 75475 Paris Cedex 10, France. philippe.chappuis@lrb.aphp.fr
authors.forename: Philippe
authors.initials: P
authors.lastname: Chappuis
authors.forename: Jacques
authors.initials: J
authors.lastname: Callebert
authors.forename: Valérie
authors.initials: V
authors.lastname: Quignon
authors.forename: France
authors.initials: F
authors.lastname: Woimant
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Laplanche
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics*; D027682:Cation Transport Proteins / Q000235:genetics*; D000073840:Copper-Transporting ATPases; D005602:France; D006527:Hepatolenticular Degeneration / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D009154:Mutation / Q000235:genetics; D016364:Reading Frames / Q000235:genetics
chemical_list: D027682:Cation Transport Proteins; D000251:Adenosine Triphosphatases; C000612464:ATP7B protein, human; D000073840:Copper-Transporting ATPases