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Genetic regulation of MUC1 alternative splicing in human tissues.

Ng W, Loh AX, Teixeira AS, Pereira SP, Swallow DM - Br. J. Cancer (2008)

Bottom Line: Splicing variation, leading to a 9-amino acid insertion in the signal peptide region, was proposed to be because of a single-nucleotide polymorphism (rs4072037) at the 5' end of exon 2, but is also reported to be cancer-associated.However, the effect of rs4072037 on this splicing event in healthy non-cancer tissues and on the additional spliceoforms ofMUC1, including those lacking the polymorphic tandem repeat (TR) domain, has never been investigated.Although there is some evidence for additional genetic and epigenetic influences, there is no indication of an effect of the TR domain on the proportions of the spliceoforms.

View Article: PubMed Central - PubMed

Affiliation: Research Department of Genetics, Evolution and Environment University College London, Wolfson House, 4 Stephenson Way, London, UK.

ABSTRACT
The membrane mucin MUC1 is aberrantly expressed in a variety of cancers, and in stomach, it is a ligand for Helicobacter pylori where it plays a role in gastric carcinogenesis. Splicing variation, leading to a 9-amino acid insertion in the signal peptide region, was proposed to be because of a single-nucleotide polymorphism (rs4072037) at the 5' end of exon 2, but is also reported to be cancer-associated. However, the effect of rs4072037 on this splicing event in healthy non-cancer tissues and on the additional spliceoforms ofMUC1, including those lacking the polymorphic tandem repeat (TR) domain, has never been investigated. Here we show that in both foetal and adult tissues of known genotype, there is clear evidence for the role of rs4072037 in controlling alternative splicing of the 5' exon 2 region of both full-length transcripts and those lacking the TR domain. Although there is some evidence for additional genetic and epigenetic influences, there is no indication of an effect of the TR domain on the proportions of the spliceoforms. In conclusion, over-representation of certain transcripts in tumour material cannot be evaluated without information on the SNP genotype as well.

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Related in: MedlinePlus

(A) MUC1 VNTR polymorphism detected on a Southern blot. The band sizes for the Raoul ladder size markers in the first and last tracks are shown on the right. Grouping of long (L) and short alleles (S) used for haplotype analysis is shown. (B) MUC1a/b transcript ratio (lung samples) plotted against MUC1TR length ratio. Similar results were obtained for stomach (data not shown).
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fig3: (A) MUC1 VNTR polymorphism detected on a Southern blot. The band sizes for the Raoul ladder size markers in the first and last tracks are shown on the right. Grouping of long (L) and short alleles (S) used for haplotype analysis is shown. (B) MUC1a/b transcript ratio (lung samples) plotted against MUC1TR length ratio. Similar results were obtained for stomach (data not shown).

Mentions: The possibility that the rate of transcript synthesis or transcript stability is affected by the variable lengths of the TR domains of MUC1 was therefore examined by testing the TR polymorphism in the same set of foetal samples and comparing allele length ratios with transcript ratios for the lung and stomach, the two tissues for which the most samples were tested. Figure 3A shows an autoradiograph of a typical Southern blot.


Genetic regulation of MUC1 alternative splicing in human tissues.

Ng W, Loh AX, Teixeira AS, Pereira SP, Swallow DM - Br. J. Cancer (2008)

(A) MUC1 VNTR polymorphism detected on a Southern blot. The band sizes for the Raoul ladder size markers in the first and last tracks are shown on the right. Grouping of long (L) and short alleles (S) used for haplotype analysis is shown. (B) MUC1a/b transcript ratio (lung samples) plotted against MUC1TR length ratio. Similar results were obtained for stomach (data not shown).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2538764&req=5

fig3: (A) MUC1 VNTR polymorphism detected on a Southern blot. The band sizes for the Raoul ladder size markers in the first and last tracks are shown on the right. Grouping of long (L) and short alleles (S) used for haplotype analysis is shown. (B) MUC1a/b transcript ratio (lung samples) plotted against MUC1TR length ratio. Similar results were obtained for stomach (data not shown).
Mentions: The possibility that the rate of transcript synthesis or transcript stability is affected by the variable lengths of the TR domains of MUC1 was therefore examined by testing the TR polymorphism in the same set of foetal samples and comparing allele length ratios with transcript ratios for the lung and stomach, the two tissues for which the most samples were tested. Figure 3A shows an autoradiograph of a typical Southern blot.

Bottom Line: Splicing variation, leading to a 9-amino acid insertion in the signal peptide region, was proposed to be because of a single-nucleotide polymorphism (rs4072037) at the 5' end of exon 2, but is also reported to be cancer-associated.However, the effect of rs4072037 on this splicing event in healthy non-cancer tissues and on the additional spliceoforms ofMUC1, including those lacking the polymorphic tandem repeat (TR) domain, has never been investigated.Although there is some evidence for additional genetic and epigenetic influences, there is no indication of an effect of the TR domain on the proportions of the spliceoforms.

View Article: PubMed Central - PubMed

Affiliation: Research Department of Genetics, Evolution and Environment University College London, Wolfson House, 4 Stephenson Way, London, UK.

ABSTRACT
The membrane mucin MUC1 is aberrantly expressed in a variety of cancers, and in stomach, it is a ligand for Helicobacter pylori where it plays a role in gastric carcinogenesis. Splicing variation, leading to a 9-amino acid insertion in the signal peptide region, was proposed to be because of a single-nucleotide polymorphism (rs4072037) at the 5' end of exon 2, but is also reported to be cancer-associated. However, the effect of rs4072037 on this splicing event in healthy non-cancer tissues and on the additional spliceoforms ofMUC1, including those lacking the polymorphic tandem repeat (TR) domain, has never been investigated. Here we show that in both foetal and adult tissues of known genotype, there is clear evidence for the role of rs4072037 in controlling alternative splicing of the 5' exon 2 region of both full-length transcripts and those lacking the TR domain. Although there is some evidence for additional genetic and epigenetic influences, there is no indication of an effect of the TR domain on the proportions of the spliceoforms. In conclusion, over-representation of certain transcripts in tumour material cannot be evaluated without information on the SNP genotype as well.

Show MeSH
Related in: MedlinePlus