title: Genotype-phenotype correlations for a wide spectrum of mutations in the Wilson disease gene (ATP7B).
abstract: Wilson disease (WND) is caused by mutations in the ATP7B gene and exhibits substantial allelic heterogeneity. In this study we report the results of molecular analyses of 20 WND families not described previously. When combined with our prior results, the cohort includes 93 index patients from 69 unrelated families. Twenty different mutations accounted for 86% of the WND chromosomes. The most frequent were p.H1069Q (35%), p.R969Q (12%), c.2530delA (7%), p.L936X (7%), p.Q289X (7%), and p.I1148T (3%). We also present here a detailed phenotypic assessment for patients whose molecular result was previously reported. Thirty cases were homozygous for 9 different mutations, 13 of which were homozygous for p.H1069Q, and 7 for p.R969Q. Mutations p.H1069Q and p.R969Q appeared to confer a milder disease as patients showed disease onset at a later age, and were associated with milder severity when found in trans with severe mutations. Predicted nonsense and frameshift mutations were associated with severe phenotypic expression with earlier disease onset and lower ceruloplasmin values. WND can be treated by copper-chelation therapy, particularly if the disease is diagnosed before irreversible tissue damage occurs. Our results on the effect of predicted nonsense and frameshift mutations are especially important for early medical intervention in presymptomatic infants and children with these genotypes.
authors.affiliation: Medical Genetics, Athens University, St. Sophia's Children's Hospital, Athens, Greece.
authors.forename: Eleni
authors.initials: E
authors.lastname: Panagiotakaki
authors.forename: Maria
authors.initials: M
authors.lastname: Tzetis
authors.forename: Nina
authors.initials: N
authors.lastname: Manolaki
authors.forename: Giorgos
authors.initials: G
authors.lastname: Loudianos
authors.forename: Athanasios
authors.initials: A
authors.lastname: Papatheodorou
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Manesis
authors.forename: Sanda
authors.initials: S
authors.lastname: Nousia-Arvanitakis
authors.forename: V
authors.initials: V
authors.lastname: Syriopoulou
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Kanavakis
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D027682:Cation Transport Proteins / Q000235:genetics*; D000073840:Copper-Transporting ATPases; D004252:DNA Mutational Analysis; D016368:Frameshift Mutation; D005838:Genotype; D006115:Greece; D006527:Hepatolenticular Degeneration / Q000235:genetics*; D006801:Humans; D009154:Mutation; D020125:Mutation, Missense; D010641:Phenotype
chemical_list: D027682:Cation Transport Proteins; D000251:Adenosine Triphosphatases; C000612464:ATP7B protein, human; D000073840:Copper-Transporting ATPases