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Mutation Analysis and the Correlation Between Genotype and Phenotype of Arg778Leu Mutation in Chinese Patients With Wilson Disease
Zhi-Ying Wu, MD, PhD;
Ning Wang, MD, PhD;
Min-Ting Lin, MD;
Ling Fang, MD, PhD;
Shen-Xing Murong, MD;
Long Yu, MD, PhD
Arch Neurol. 2001;58:971-976.
Background The defective gene (ATP7B) that causes Wilson disease (WD)
codes for a putative copper-transporting P-type adenosine triphosphatase.
After cloning of ATP7B, the spectrum of mutations and their clinical
consequences have been investigated in patients with WD in different ethnic
populations. However, the spectrum of mutations and the correlation of genotype-phenotype
in the Chinese population have not been extensively studied.
Objective To investigate the characterization of mutations of ATP7B
and the correlation between genotype and phenotype in the Chinese population.
Methods We studied 60 unrelated healthy Chinese and 65 unrelated Chinese families,
including 84 patients with WD and 126 parents. Genomic DNA was prepared from
peripheral blood leukocytes using a salt-precipitation method. Polymerase
chain reaction single-strand conformation polymorphism and subsequent direct
sequencing were used to identify the mutations and polymorphisms of ATP7B. Statistical analysis was performed using t test
or  2 test.
Results We identified 18 mutations (7 novel) and 11 polymorphisms (3 novel).
The novel mutations are -36C T, Trp650ter, Gln914ter, 2810delT,
Thr935Met, Arg1041Pro, and Glu1173Lys. The novel polymorphisms are 1168AG
(Ile390Val), 2785AG (Ile929Val), and 3316GA (Val1106Ile). Two
mutations, Arg778Leu and Thr935Met, are relatively frequent, representing
37.7% and 10.0% of patients, respectively. To our knowledge, we are the first
to report the correlation between the genotype and phenotype of Arg778Leu.
The result shows that Arg778Leu homozygotes are associated with the early
onset of WD with hepatic presentation.
Conclusions The Arg778Leu and Thr935Met mutations are hot spots in the Chinese population.
The features of mutations of ATP7B differ between the Chinese
and Western ethnic populations. The Arg778Leu mutation has severe effects
on the function of ATP7B. These findings are valuable for developing
a fast and effective method to diagnose the presence of the WD gene.
From the Department of Neurology (Drs Wu, Wang, Fang, and Murong) and
the Institute of Neurological Sciences (Dr Lin), First Affiliated Hospital,
Fujian Medical University, Fuzhou, and the Institute of Genetics, Fudan University,
Shanghai (Dr Yu), People's Republic of China.
Corresponding author and reprints: Zhi-Ying Wu, MD, PhD, Department
of Neurology, First Affiliated Hospital, Fujian Medical University, 20 Chazhong
Rd, Fuzhou 350005, People's Republic of China (e-mail: zhiyingwu67{at}yahoo.com).
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