High prevalence of the H1069Q mutation in East German patients with Wilson disease: rapid detection of mutations by limited sequencing and phenotype-genotype analysis.
OBJECTIVE
Wilson disease is caused by a large number of different mutations in the ATP7B gene. Wilson disease patients from a homogeneous ethnical background (Saxonia) were studied for distribution and phenotypes of ATP7B mutations.


METHODS
Eighty-two patients were analyzed. The H1069Q mutation was assayed by a polymerase chain reaction-based restriction fragment length polymorphism test. Exons 8 and 15 were sequenced in all, and the entire gene in 30, non-H1069Q-homozygotes.


RESULTS
Four novel and 12 known mutations were found. Thirty-two (39%) Wilson disease patients were homozygous and 39 (48%) heterozygous for the H1069Q mutation (allele frequency 63%). Together with sequence analysis of exons 8 and 15 mutations in both alleles were identified in 65% of patients. Only one patient had both mutations at other locations. In H1069Q homozygotes symptoms started later (21.3+/-7.2 years) than in H1069Q compound heterozygotes (14.6+/-5.8, P<0.001) or H1069Q negatives (10+/-4.4, P<0.001), and they had more frequently neurologic symptoms (93 vs. 47%, P<0.001) and Kayser-Fleischer rings (82 vs. 51%, P<0.001). Mutation status did not correlate with liver biopsy findings, serum ceruloplasmin levels or (64)Cu-assay results.


CONCLUSIONS
In spite of many known ATP7B mutations, only few occur in this homogeneous population. Limited genetic testing is useful to confirm Wilson disease in this population.
Caca
K
K
Department of Medicine II, University of Leipzig, Philipp-Rosenthal-Strasse 27, 04103 Leipzig, Germany. caca@medizin.uni-leipzig.de
Ferenci
P
P
Kühn
H J
HJ
Polli
C
C
Willgerodt
H
H
Kunath
B
B
Hermann
W
W
Mössner
J
J
Berr
F
F
D000251:Adenosine Triphosphatases / Q000737:chemistry / Q000235:genetics*; D019943:Amino Acid Substitution; D027682:Cation Transport Proteins / Q000737:chemistry / Q000235:genetics*; D003300:Copper / Q000378:metabolism; D000073840:Copper-Transporting ATPases; D005091:Exons; D005838:Genotype; D005858:Germany; D006527:Hepatolenticular Degeneration / Q000235:genetics*; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D009154:Mutation; D010641:Phenotype; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D044465:White People
D027682:Cation Transport Proteins; D003300:Copper; D000251:Adenosine Triphosphatases; C000612464:ATP7B protein, human; D000073840:Copper-Transporting ATPases