Abnormal mRNA splicing resulting from consensus sequence splicing mutations of ATP7B

被引:28
作者
Loudianos, G
Lovicu, M
Dessi, V
Tzetis, M
Kanavakis, E
Zancan, L
Zelante, L
Galvèz-Galvèz, C
Cao, A
机构
[1] Osped Reg Microcitemie, I-09131 Cagliari, Italy
[2] Univ Cagliari, Dipartimento Sci Biomed & Biotecnol, Cagliari, Italy
[3] Univ Athens, Dept Pediat 1, Athens, Greece
[4] Univ Padua, Dipartimento Pediat, Clin Pediat 1, I-35128 Padua, Italy
[5] Osped San Giovanni Rotondo, Serv Genet Med, IRCCS, San Giovanni Rotondo, Italy
[6] Hosp Mil Sevilla, Serv Neurol, Seville, Spain
[7] CNR, IRTAM, Cagliari, Italy
关键词
Wilson disease; WD; ATP7B; molecular analysis; alternative splicing;
D O I
10.1002/humu.10121
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
More than 200 Wilson disease (WD) disease-causing mutations have been defined to date. Missense mutations are largely prevalent while splice,site mutations are limited in number. Most reside in the splice donor or acceptor sites and only a minority are detected in splicing consensus sequences. Furthermore, only a few splicing mutations have been studied at the RNA level to date. In this study, using the RT-PCR method we performed the molecular characterization of four consensus splice site mutations identified by DNA analysis in patients with WD. One of them, previously described 1707 + 3insT, occurred at position 3 in the donor splice site of intron 4, while the other three, 2122-8T>G, 2866-6T>G, and 3061-12T>A, are novel and occurred in the acceptor splice sites of introns 7, 12, and 13, respectively. Analysis revealed a prevalently abnormal splicing in the samples carrying the mutations compared to the normal controls. Comparison of RNA splicing with normal controls in liver and lymphocytes further suggests that abnormal splicing of the WD gene is also present and differentially regulated in normal tissues. The results produced in this study strongly suggest that DNA mutations residing in the consensus sequence of WD gene splice sites result in the WD phenotype by interfering with the production of the normal WD protein. Further studies are necessary to better quantify the amount of different transcripts produced by these mutations, and establish their correlation with the disease phenotype.
引用
收藏
页码:260 / 266
页数:7
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