Abnormal mRNA splicing resulting from consensus sequence splicing mutations of ATP7B

G. Loudianos, M. Lovicu, V. Dessi, M. Tzetis, E. Kanavakis, L. Zancan, L. Zelante, C. Galvèz-Galvèz, A. Cao

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)260-266
Number of pages7
JournalHuman Mutation
Volume20
Issue number4
DOIs
Publication statusPublished - 2002

Fingerprint

Consensus Sequence
Hepatolenticular Degeneration
RNA Splice Sites
Messenger RNA
Mutation
Introns
RNA Splicing
Phenotype
DNA
Missense Mutation
Genes
Lymphocytes
RNA
Polymerase Chain Reaction
Liver

Keywords

  • Alternative splicing
  • ATP7B
  • Molecular analysis
  • WD
  • Wilson disease

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Loudianos, G., Lovicu, M., Dessi, V., Tzetis, M., Kanavakis, E., Zancan, L., ... Cao, A. (2002). Abnormal mRNA splicing resulting from consensus sequence splicing mutations of ATP7B. Human Mutation, 20(4), 260-266. https://doi.org/10.1002/humu.10121

Abnormal mRNA splicing resulting from consensus sequence splicing mutations of ATP7B. / Loudianos, G.; Lovicu, M.; Dessi, V.; Tzetis, M.; Kanavakis, E.; Zancan, L.; Zelante, L.; Galvèz-Galvèz, C.; Cao, A.

In: Human Mutation, Vol. 20, No. 4, 2002, p. 260-266.

Research output: Contribution to journalArticle

Loudianos, G, Lovicu, M, Dessi, V, Tzetis, M, Kanavakis, E, Zancan, L, Zelante, L, Galvèz-Galvèz, C & Cao, A 2002, 'Abnormal mRNA splicing resulting from consensus sequence splicing mutations of ATP7B', Human Mutation, vol. 20, no. 4, pp. 260-266. https://doi.org/10.1002/humu.10121
Loudianos G, Lovicu M, Dessi V, Tzetis M, Kanavakis E, Zancan L et al. Abnormal mRNA splicing resulting from consensus sequence splicing mutations of ATP7B. Human Mutation. 2002;20(4):260-266. https://doi.org/10.1002/humu.10121
Loudianos, G. ; Lovicu, M. ; Dessi, V. ; Tzetis, M. ; Kanavakis, E. ; Zancan, L. ; Zelante, L. ; Galvèz-Galvèz, C. ; Cao, A. / Abnormal mRNA splicing resulting from consensus sequence splicing mutations of ATP7B. In: Human Mutation. 2002 ; Vol. 20, No. 4. pp. 260-266.
@article{8ca210cc4a1540689ccf3560b37581a2,
title = "Abnormal mRNA splicing resulting from consensus sequence splicing mutations of ATP7B",
abstract = "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.",
keywords = "Alternative splicing, ATP7B, Molecular analysis, WD, Wilson disease",
author = "G. Loudianos and M. Lovicu and V. Dessi and M. Tzetis and E. Kanavakis and L. Zancan and L. Zelante and C. Galv{\`e}z-Galv{\`e}z and A. Cao",
year = "2002",
doi = "10.1002/humu.10121",
language = "English",
volume = "20",
pages = "260--266",
journal = "Human Mutation",
issn = "1059-7794",
publisher = "John Wiley and Sons Inc.",
number = "4",

}

TY - JOUR

T1 - Abnormal mRNA splicing resulting from consensus sequence splicing mutations of ATP7B

AU - Loudianos, G.

AU - Lovicu, M.

AU - Dessi, V.

AU - Tzetis, M.

AU - Kanavakis, E.

AU - Zancan, L.

AU - Zelante, L.

AU - Galvèz-Galvèz, C.

AU - Cao, A.

PY - 2002

Y1 - 2002

N2 - 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.

AB - 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.

KW - Alternative splicing

KW - ATP7B

KW - Molecular analysis

KW - WD

KW - Wilson disease

UR - http://www.scopus.com/inward/record.url?scp=0036390072&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0036390072&partnerID=8YFLogxK

U2 - 10.1002/humu.10121

DO - 10.1002/humu.10121

M3 - Article

VL - 20

SP - 260

EP - 266

JO - Human Mutation

JF - Human Mutation

SN - 1059-7794

IS - 4

ER -