Journal Article

Mutations in DPC4 (SMAD4) Cause Juvenile Polyposis Syndrome, But Only Account for a Minority of Cases

Richard Houlston, Stephen Bevan, Andrew Williams, Joanne Young, Malcolm Dunlop, Paul Rozen, Charis Eng, David Markie, Kelly Woodford-Richens, Miguel A. Rodriguez-Bigas, Barbara Leggett, Kay Neale, Robin Phillips, Eamon Sheridan, Shirley Hodgson, Takeo Iwama, Diana Eccles, Walter Bodmer and Ian Tomlinson

in Human Molecular Genetics

Volume 7, issue 12, pages 1907-1912
Published in print November 1998 | ISSN: 0964-6906
Published online November 1998 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/7.12.1907
Mutations in DPC4 (SMAD4) Cause Juvenile Polyposis Syndrome, But Only Account for a Minority of Cases

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Juvenile polyps are present in a number of Mendelian disorders, sometimes in association only with gastrointestinal cancer [juvenile polyposis syndrome (JPS)] and sometimes as part of known syndromes (Cowden, Gorlin and Banayan-Zonana) in association with developmental abnormalities, dysmorphic features or extra-intestinal tumours. Recently, a gene for JPS was mapped to 18q21.1 and the candidate gene DPC4 (SMAD4) was shown to carry frameshift mutations in some JPS families. We have analysed eight JPS families for linkage to DPC4. Overall, there was no evidence for linkage to DPC4; linkage could be excluded in two of the eight pedigrees and was unlikely in two others. We then tested these eight families and a further 13 familial and sporadic JPS cases for germline mutations in DPC4. Just one germline DPC4 mutation was found (in a familial JPS patient from a pedigree unsuitable for linkage analysis). Like all three previously reported germline mutations, this variant occurred towards the C-terminus of the DPC4 protein. However, our patient's mutation is a missense change (R361C); somatic missense mutations in DPC4 have been reported previously in tumours. We therefore confirm DPC4 as a cause of JPS, but show that there is considerable remaining, uncharacterized genetic heterogeneity in this disease.

Journal Article.  2857 words.  Illustrated.

Subjects: Genetics and Genomics

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