TY - JOUR
TI - Genotype-phenotype correlations for a wide spectrum of mutations in the
Wilson disease gene (ATP7B)
AU - Panagiotakaki, E
AU - Tzetis, M
AU - Manolaki, N
AU - Loudianos, G and
AU - Papatheodorou, A
AU - Manesis, E
AU - Nousia-Arvanitakis, S and
AU - Syriopoulou, V
AU - Kanavakis, E
JO - American Journal of Medical Genetics. Part A
PY - 2004
VL - 131A
TODO - 2
SP - 168-173
PB - Wiley
SN - 1552-4825, 1552-4833
TODO - 10.1002/ajmg.a.30345
TODO - molecular genetic diagnosis; Wilson disease; mutations;
genotype-phenotype; ATP7B
TODO - 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. (C) 2004 Wiley-Liss, Inc.
ER -