Novel mutations of the ATP7B gene among 109 Hungarian patients with Wilson's disease.
OBJECTIVE
Diagnosis of Wilson's disease may be difficult in patients presenting with liver disease and in asymptomatic siblings. The aim of the present study was to assess the impact of genetic testing for diagnosis of the disease in a large cohort (n=109) from Hungary.


METHODS
One hundred and nine patients with Wilson's disease were studied (65 men and 44 women; mean age at onset of symptoms: 20+/-9 years). Diagnosis of the disease was based on typical clinical and laboratory features (all had a Wilson's disease score of >or=4). H1069Q was assessed by the semi-nested polymerase chain reaction-based restriction fragment length polymorphism assay. H1069Q heterozygotes and H1069Q negative samples were then screened for mutations (on exons 6 to 20) by denaturating high-performance liquid chromatography and than sequenced on a genetic analyser.


RESULTS
Twenty-three different mutations were found. H1069Q was the most frequent mutation in Hungary, detected in 77 patients (71%). Fourteen further known mutations were found by sequencing. We identified eight new mis-sense mutations not described before: N676I, S693Y, Y715H, M769L, W939C, P1273S, G1281D and G1341V. In 36/109 patients (33%) the diagnosis of Wilson's disease was established by adding mutational analysis. The Kayser-Fleischer ring was more frequent in H1069Q homozygous patients and their mean age at the time of diagnosis was higher than in patients heterozygous or negative for H1069Q.


CONCLUSIONS
Eight novel mutations in addition to the 15 that are already known were found in Hungarian patients with Wilson's disease. Our results underline the importance and usefulness of genetic testing for patients presenting with liver disease and for family screening.
Folhoffer
Aniko
A
First Department of Internal Medicine, Semmelweis University, Budapest, Hungary.
Ferenci
Peter
P
Csak
Timea
T
Horvath
Andrea
A
Hegedus
Dalma
D
Firneisz
Gabor
G
Osztovits
Janos
J
Kosa
Janos Pal
JP
Willheim-Polli
Claudia
C
Szonyi
Laszlo
L
Abonyi
Margit
M
Lakatos
Peter Laszlo
PL
Szalay
Ferenc
F
D000251:Adenosine Triphosphatases / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D017677:Age Distribution; D017668:Age of Onset; D027682:Cation Transport Proteins / Q000235:genetics*; D002648:Child; D015331:Cohort Studies; D000073840:Copper-Transporting ATPases; D004252:DNA Mutational Analysis / Q000379:methods; D005260:Female; D005820:Genetic Testing / Q000379:methods; D006527:Hepatolenticular Degeneration / Q000175:diagnosis / Q000235:genetics*; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D016133:Polymerase Chain Reaction / Q000379:methods
D027682:Cation Transport Proteins; D000251:Adenosine Triphosphatases; C000612464:ATP7B protein, human; D000073840:Copper-Transporting ATPases