Distinct clinical courses according to presenting phenotypes and their correlations to ATP7B mutations in a large Wilson's disease cohort
Correction(s) for this article
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CORRIGENDA
- Volume 31Issue 8Liver International
- pages: 1242-1242
- First Published online: May 20, 2011
Beom H. Lee
Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
Department of Pediatrics, Genome Research Center for Birth Defects and Genetic Disorders, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
Medical Genetics Clinic and Laboratory, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
*Contributed equally.
Search for more papers by this authorJoo H. Kim
Department of Pediatrics, Genome Research Center for Birth Defects and Genetic Disorders, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
*Contributed equally.
Search for more papers by this authorSun Y. Lee
Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
Search for more papers by this authorHye Y. Jin
Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
Search for more papers by this authorKwi-Joo Kim
Department of Pediatrics, Genome Research Center for Birth Defects and Genetic Disorders, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
Search for more papers by this authorJin-Joo Lee
Medical Genetics Clinic and Laboratory, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
Search for more papers by this authorJung-Young Park
Department of Pediatrics, Genome Research Center for Birth Defects and Genetic Disorders, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
Search for more papers by this authorGu-Hwan Kim
Department of Pediatrics, Genome Research Center for Birth Defects and Genetic Disorders, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
Medical Genetics Clinic and Laboratory, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
Search for more papers by this authorJin-Ho Choi
Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
Search for more papers by this authorKyung M. Kim
Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
Search for more papers by this authorHan-Wook Yoo
Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
Department of Pediatrics, Genome Research Center for Birth Defects and Genetic Disorders, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
Medical Genetics Clinic and Laboratory, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
Search for more papers by this authorBeom H. Lee
Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
Department of Pediatrics, Genome Research Center for Birth Defects and Genetic Disorders, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
Medical Genetics Clinic and Laboratory, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
*Contributed equally.
Search for more papers by this authorJoo H. Kim
Department of Pediatrics, Genome Research Center for Birth Defects and Genetic Disorders, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
*Contributed equally.
Search for more papers by this authorSun Y. Lee
Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
Search for more papers by this authorHye Y. Jin
Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
Search for more papers by this authorKwi-Joo Kim
Department of Pediatrics, Genome Research Center for Birth Defects and Genetic Disorders, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
Search for more papers by this authorJin-Joo Lee
Medical Genetics Clinic and Laboratory, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
Search for more papers by this authorJung-Young Park
Department of Pediatrics, Genome Research Center for Birth Defects and Genetic Disorders, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
Search for more papers by this authorGu-Hwan Kim
Department of Pediatrics, Genome Research Center for Birth Defects and Genetic Disorders, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
Medical Genetics Clinic and Laboratory, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
Search for more papers by this authorJin-Ho Choi
Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
Search for more papers by this authorKyung M. Kim
Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
Search for more papers by this authorHan-Wook Yoo
Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
Department of Pediatrics, Genome Research Center for Birth Defects and Genetic Disorders, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
Medical Genetics Clinic and Laboratory, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
Search for more papers by this authorAbstract
Introduction and aims: Wide phenotypic and genotypic heterogeneities in Wilson's disease (WD) have been reported, hampering the study of their correlations. The goal of this study was to identify the factors related to these diversities.
Methods: Clinical courses and molecular genetic characteristics were analysed in 237 unrelated Korean WD families. The average follow-up period was 8.2 ± 5.8 years.
Results: Presenting phenotypes were classified as H1 (12.2%), H2 (42.4%), N1 (21.6%), N2 (0.4%), NX (0.4%), presymptomatic (22.4%) and other (0.4%), modifying the guidelines by Ferenci and colleagues. Age at presentation was youngest and cirrhosis was rarest in the presymptomatic group. Decompensated cirrhosis was the highest in the H1 group. Favourable outcome was rarest in the N1 group. Forty-seven (11 novel) ATP7B mutations were identified in 85% of the 474 alleles. Multiplex ligation-dependent probe amplification assays in ATP7B and analyses of ATOX1 and COMMD1 genes identified no additional mutations. Yeast complementation assays demonstrated functional perturbation of the seven novel missense mutants. Five major mutations, p.Arg778Leu, p.Ala874Val, p.Asn1270Ser, p.Lys838SerfsX35 and p.Leu1083Phe, accounted for 63% of the alleles. H1 was more common, age at presentation was younger and N1+N2+NX tended to be less common in patients with nonsense, frame shifting or splicing mutations than in those with missense mutations alone. Patients with both mutations in the transduction (Td) or the ATP hinge domain showed presymptomatic or hepatic manifestations but no neurological manifestation.
Conclusions: The presenting phenotype strongly affects the clinical outcome of WD, and is related to the ATP7B mutation type and location, providing an evidence for genotype–phenotype correlations in WD.
Supporting Information
Fig. S1. Yeast complementation assay. The Δccc2 yeast strain was transformed with wild-type ATP7B (a), vector only (b), the SNP p.Val456Leu (c), the mutant p.Arg778Leu (d), as positive/negative controls, or with each of seven novel missense variants: p.Pro410Leu (e), p.Val734Phe (f), p.Arg827Trp (g), p.Lys1010Thr (h), p.His1069Tyr (i), p.Arg1151Cys (j) and p.Ala1295Asp (k). Yeast were cultured in the absence of chelators (A), the presence 150 μM BCS to chelate copper (-Cu2+), (B) 150 μM ferrozine to chelate iron (-Fe2+) (C), or 150 μM BCS and 150 μM ferrozine to chelate both copper and iron (-Cu2+, -Fe2+) (D).
Fig. S2. Growth curve analysis in iron-limited (100 μM ferrozine) media. Yeasts were grown at 30°C for 82 hours with measurement of OD600 nm at 0, 20, 40, 60, and 82 hours. The Δccc2 yeast strain was transformed with wild-type ATP7B (a), the SNP p.Val456Leu (b), two previously-known mutants, p.Arg778Leu (c) and p.Cys656X (d), or each of seven novel missense variants: p.Pro410Leu (e), p.Val734Phe (f), p.Arg827Trp (g), p.Lys1010Thr (h), p.His1069Tyr (i), p.Arg1151Cys (j), and p.Ala1295Asp (k).
Table S1. Clinical findings at presentation in patients with Wilson disease.
Table S2. The mutations of the ATP7B gene in Korean Wilson disease patients. aTotal number of the alleles was 474. *, novel mutation; n.d., not-done; Cu, copper-binding domain; Tm, transmembrane domain; Td, transduction; Ph, phosphorylation domain. SIFT: http://blocks.fhcrc.org/sift/SIFT.html. Polyphen: http://genetics.bwh.harvard.edu/pph/.
Table S3. Clinical presentations of patients with both ATP7B alleles mutated in the same domain. Tm, transmembrane domain; Td, transduction domain; Ph, phosphorylation; H, hepatic presentation; and N, neurological presentation.
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