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Clinical and molecular characterization of Wilson's disease in China: identification of 14 novel mutations.

Li XH, Lu Y, Ling Y, Fu QC, Xu J, Zang GQ, Zhou F, De-Min Y, Han Y, Zhang DH, Gong QM, Lu ZM, Kong XF, Wang JS, Zhang XX - BMC Med. Genet. (2011)

Bottom Line: Homozygous p.Arg778Leu and nonsense mutation/frameshift mutations were more often associated with primary hepatic manifestations (p = 0.0286 and p = 0.0383, respectively) and higher alanine transaminase levels at diagnosis (p = 0.0361 and p = 0.0047, respectively).Nonsense mutation/frameshift mutations were also associated with lower serum ceruloplasmin (p = 0.0065). we identified 14 novel mutations and found that the spectrum of mutations of ATP7B in China is quite distinct from that of Western countries.Four exons (8, 12, 13, and 16) and two mutations (p.Arg778Leu, p.Pro992Leu) should be considered high priority for cost-effective testing in China.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.

ABSTRACT

Background: Wilson's disease (WND) is a rare autosomal recessive disorder. Here we have evaluated 62 WND cases (58 probands) from the Chinese Han population to expand our knowledge of ATP7B mutations and to more completely characterize WND in China.

Methods: the coding and promoter regions of the ATP7B gene were analyzed by direct sequencing in 62 Chinese patients (58 probands) with WND (male, n = 37; female, n = 25; age range, 2 ~ 61 years old).

Results: neurologic manifestations were associated with older age at diagnosis (p < 0.0001) and longer diagnostic delay (p < 0.0001). Age at diagnosis was also correlated with urinary copper concentration (r = 0.58, p < 0.001). Forty different mutations, including 14 novel mutations, were identified in these patients. Common mutations included p.Arg778Leu (31.9%) and p.Pro992Leu (11.2%). Homozygous p.Arg778Leu and nonsense mutation/frameshift mutations were more often associated with primary hepatic manifestations (p = 0.0286 and p = 0.0383, respectively) and higher alanine transaminase levels at diagnosis (p = 0.0361 and p = 0.0047, respectively). Nonsense mutation/frameshift mutations were also associated with lower serum ceruloplasmin (p = 0.0065).

Conclusions: we identified 14 novel mutations and found that the spectrum of mutations of ATP7B in China is quite distinct from that of Western countries. The mutation type plays a role in predicting clinical manifestations. Genetic testing is a valuable tool to detect WND in young children, especially in patients younger than 8 years old. Four exons (8, 12, 13, and 16) and two mutations (p.Arg778Leu, p.Pro992Leu) should be considered high priority for cost-effective testing in China.

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Correlation of severe mutations (SMs) with clinical manifestations (A), corneal Kayser-Fleischer ring (B), ALT levels at diagnosis (C) and serum ceruloplasmin (D). SM, nonsense mutation and frameshift mutations; missense mutations (MM); SM/SM, patients possessing two severe mutations; SM/MM, patients possessing one severe and one missense mutation; MM/MM, patients possessing two missense mutations.
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Figure 7: Correlation of severe mutations (SMs) with clinical manifestations (A), corneal Kayser-Fleischer ring (B), ALT levels at diagnosis (C) and serum ceruloplasmin (D). SM, nonsense mutation and frameshift mutations; missense mutations (MM); SM/SM, patients possessing two severe mutations; SM/MM, patients possessing one severe and one missense mutation; MM/MM, patients possessing two missense mutations.

Mentions: All four patients in the SM/SM group presented with hepatic manifestations (H1 or H2) and one patient presented with acute liver failure; statistics showed significant differences among the three groups (p = 0.0383; Figure 7A). The SM/SM group showed higher ALT levels (p = 0.0061; Figure 7C), lower rate of K-F ring detection (p = 0.0304; Figure 7B), and lower serum ceruloplasmin levels at diagnosis than other groups (p = 0.0065; Figure 7D,). No significant difference was observed for age at symptom onset, diagnostic delay, age at diagnosis, or urinary copper levels (Additional file 1 : Supplementary Table S5).


Clinical and molecular characterization of Wilson's disease in China: identification of 14 novel mutations.

Li XH, Lu Y, Ling Y, Fu QC, Xu J, Zang GQ, Zhou F, De-Min Y, Han Y, Zhang DH, Gong QM, Lu ZM, Kong XF, Wang JS, Zhang XX - BMC Med. Genet. (2011)

Correlation of severe mutations (SMs) with clinical manifestations (A), corneal Kayser-Fleischer ring (B), ALT levels at diagnosis (C) and serum ceruloplasmin (D). SM, nonsense mutation and frameshift mutations; missense mutations (MM); SM/SM, patients possessing two severe mutations; SM/MM, patients possessing one severe and one missense mutation; MM/MM, patients possessing two missense mutations.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3025937&req=5

Figure 7: Correlation of severe mutations (SMs) with clinical manifestations (A), corneal Kayser-Fleischer ring (B), ALT levels at diagnosis (C) and serum ceruloplasmin (D). SM, nonsense mutation and frameshift mutations; missense mutations (MM); SM/SM, patients possessing two severe mutations; SM/MM, patients possessing one severe and one missense mutation; MM/MM, patients possessing two missense mutations.
Mentions: All four patients in the SM/SM group presented with hepatic manifestations (H1 or H2) and one patient presented with acute liver failure; statistics showed significant differences among the three groups (p = 0.0383; Figure 7A). The SM/SM group showed higher ALT levels (p = 0.0061; Figure 7C), lower rate of K-F ring detection (p = 0.0304; Figure 7B), and lower serum ceruloplasmin levels at diagnosis than other groups (p = 0.0065; Figure 7D,). No significant difference was observed for age at symptom onset, diagnostic delay, age at diagnosis, or urinary copper levels (Additional file 1 : Supplementary Table S5).

Bottom Line: Homozygous p.Arg778Leu and nonsense mutation/frameshift mutations were more often associated with primary hepatic manifestations (p = 0.0286 and p = 0.0383, respectively) and higher alanine transaminase levels at diagnosis (p = 0.0361 and p = 0.0047, respectively).Nonsense mutation/frameshift mutations were also associated with lower serum ceruloplasmin (p = 0.0065). we identified 14 novel mutations and found that the spectrum of mutations of ATP7B in China is quite distinct from that of Western countries.Four exons (8, 12, 13, and 16) and two mutations (p.Arg778Leu, p.Pro992Leu) should be considered high priority for cost-effective testing in China.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.

ABSTRACT

Background: Wilson's disease (WND) is a rare autosomal recessive disorder. Here we have evaluated 62 WND cases (58 probands) from the Chinese Han population to expand our knowledge of ATP7B mutations and to more completely characterize WND in China.

Methods: the coding and promoter regions of the ATP7B gene were analyzed by direct sequencing in 62 Chinese patients (58 probands) with WND (male, n = 37; female, n = 25; age range, 2 ~ 61 years old).

Results: neurologic manifestations were associated with older age at diagnosis (p < 0.0001) and longer diagnostic delay (p < 0.0001). Age at diagnosis was also correlated with urinary copper concentration (r = 0.58, p < 0.001). Forty different mutations, including 14 novel mutations, were identified in these patients. Common mutations included p.Arg778Leu (31.9%) and p.Pro992Leu (11.2%). Homozygous p.Arg778Leu and nonsense mutation/frameshift mutations were more often associated with primary hepatic manifestations (p = 0.0286 and p = 0.0383, respectively) and higher alanine transaminase levels at diagnosis (p = 0.0361 and p = 0.0047, respectively). Nonsense mutation/frameshift mutations were also associated with lower serum ceruloplasmin (p = 0.0065).

Conclusions: we identified 14 novel mutations and found that the spectrum of mutations of ATP7B in China is quite distinct from that of Western countries. The mutation type plays a role in predicting clinical manifestations. Genetic testing is a valuable tool to detect WND in young children, especially in patients younger than 8 years old. Four exons (8, 12, 13, and 16) and two mutations (p.Arg778Leu, p.Pro992Leu) should be considered high priority for cost-effective testing in China.

Show MeSH
Related in: MedlinePlus