Mutational analysis of 65 Wilson disease patients in Hong Kong Chinese: identification of 17 novel mutations and its genetic heterogeneity.
Wilson disease (WD), an autosomal recessive disorder of copper transport, is the most common inherited liver disorder in Hong Kong Chinese. This was the first local study to elucidate the molecular basis and establish an effective DNA-based diagnostic protocol. The ATP7B genes of 65 patients were amplified by polymerase chain reaction (PCR) and sequenced. Haplotype analysis was performed using D13S301, D13S314, and D13S316. The p.L770L/p.R778L status in 660 subjects was determined to estimate WD prevalence. Allele age of p.R778L was determined by the smallest homozygosity region between D13S301 and D13S270. We identified 42 different mutations with 17 being novel. p.R778L (17.3%) was the most prevalent. Exons 2, 8, 12, 13, and 16 harbored 70% mutations. Thirty-two haplotypes were associated with WD chromosomes. The estimated prevalence rate was 1 in 5,400. Three out of 660 normal subjects had p.L770L/p.R778L. In the remaining 657 individuals, neither p.L770L nor p.R778L was found. We characterized a Hong Kong Chinese-specific ATP7B mutation spectrum with great genetic diversity. Exons 2, 8, 12, 13, and 16 should be screened first. The perfect linkage disequilibrium suggested that p.R778L and its private polymorphism p.L770L originated from a single ancestor. This East-Asian-specific mutation p.R778L/p.L770L is aged at least 5,500 years.
Mak
Chloe Miu
CM
Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China.|Division of Clinical Biochemistry, Queen Mary Hospital, Hong Kong, China.
Lam
Ching-Wan
CW
Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China. ching-wanlam@cuhk.edu.hk.
Tam
Sidney
S
Division of Clinical Biochemistry, Queen Mary Hospital, Hong Kong, China.
Lai
Ching-Lung
CL
Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China.
Chan
Lik-Yuen
LY
Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China.
Fan
Sheung-Tat
ST
Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China.
Lau
Yu-Lung
YL
Department of Pediatrics and Adolescent Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China.
Lai
Jak-Yiu
JY
Department of Medicine, Princess Margaret Hospital, Hong Kong, China.
Yuen
Patrick
P
Department of Pediatrics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China.
Hui
Joannie
J
Department of Pediatrics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China.
Fu
Chun-Cheung
CC
Department of Pediatrics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China.
Wong
Ka-Sing
KS
Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China.
Mak
Wing-Lai
WL
Department of Pathology, Tuen Mun Hospital, Hong Kong, China.
Tze
Kong
K
Department of Pediatrics, Tuen Mun Hospital, Hong Kong, China.
Tong
Sui-Fan
SF
Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China.
Lau
Abby
A
Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China.
Leung
Nancy
N
Department of Medicine, Alice Ho Miu Ling Nethersole Hospital, Hong Kong, China.
Hui
Aric
A
Department of Medicine, Alice Ho Miu Ling Nethersole Hospital, Hong Kong, China.
Cheung
Ka-Ming
KM
Department of Pediatrics and Adolescent Medicine, Caritas Medical Center, Hong Kong, China.
Ko
Chun-Hung
CH
Department of Pediatrics and Adolescent Medicine, Caritas Medical Center, Hong Kong, China.
Chan
Yiu-Ki
YK
Department of Medicine and Geriatrics, Caritas Medical Centre, Sham Shui Po, Hong Kong, China.
Ma
Oliver
O
Division of Clinical Biochemistry, Queen Mary Hospital, Hong Kong, China.
Chau
Tai-Nin
TN
Department of Medicine and Geriatrics, United Christian Hospital, Hong Kong, China.
Chiu
Alexander
A
Department of Adult Intensive Care Unit, Queen Mary Hospital, Hong Kong, China.
Chan
Yan-Wo
YW
Department of Pathology, Princess Margaret Hospital, Hong Kong, China.
D044466:Asian People; D004252:DNA Mutational Analysis; D005787:Gene Frequency; D018740:Genetic Heterogeneity; D006239:Haplotypes; D006527:Hepatolenticular Degeneration / Q000235:genetics*; D006723:Hong Kong; D006801:Humans; D015810:Linkage Disequilibrium; D009154:Mutation