[Haplotype analysis and possible founder effect at the R778L mutation of the ATP7B gene in Korean patients with Wilson's disease].
OBJECTIVE
Wilson's disease (WD) is an inherited disorder of copper metabolism caused by alteration of the P-type adenosine triphosphatase (ATP) 7B gene. In this study, we analyzed the frequency of well-known mutations and constructed the first haplotypes for Koreans. In addition, we evaluated whether a founder effect existed in Korean patients with WD.


METHODS
We obtained DNA samples from 21 patients with WD and their parents (total cohort n=63). ATP7B gene mutations were identified by direct sequencing methods, and microsatellite typing was performed at D13S315, D13S1325, and D13S316 with fluorescent dye-labeled primers. Any founder effect was identified by using 42 normal alleles from parents with a normal phenotype as a control group. The chi square test and Fisher's exact test were used for statistical analysis.


RESULTS
Three common mutations were found in 23 chromosomes obtained from 21 patients: the R778L mutation at exon 8 (15/23, 65.2%), the A874V mutation at exon 11 (6/23, 26.1%), and the N1270S mutation at exon 18 (2/23, 8.7%). D13S315 and D13S316 showed linkage disequilibrium at alleles 5 and 4, respectively, in patients with the R778L mutation (P=0.0157 and 0.0001, respectively). The haplotype made up of these two alleles occurred significantly more frequently in patients with the R778L mutation (5-R778L-4, D13S315-mutation-D13S316) than in the controls (P=0.0018).


CONCLUSIONS
The arche haplotype of the ATP7B gene in Korean patients with WD may be 5-R778L-4 (D13S315.mutation.D13S316), and it might illustrate a founder effect.
Division of Pediatric Gastroenterology, Hepatology and Nutrition, School of Medicine, Seoul National University, Korea.
Sun Hwan
SH
Bae
Jong Won
JW
Kim
Jeong Kee
JK
Seo
D000251:Adenosine Triphosphatases / Q000235:genetics*; D019943:Amino Acid Substitution; D027682:Cation Transport Proteins / Q000235:genetics*; D000073840:Copper-Transporting ATPases; D018703:Founder Effect; D005787:Gene Frequency; D005838:Genotype; D006239:Haplotypes; D006527:Hepatolenticular Degeneration / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D018895:Microsatellite Repeats; D009154:Mutation; D056910:Republic of Korea
D027682:Cation Transport Proteins; D000251:Adenosine Triphosphatases; C000612464:ATP7B protein, human; D000073840:Copper-Transporting ATPases