Common Deletion of SMAD4 in Juvenile Polyposis Is a Mutational Hotspot

James R Howe; Jason Shellnut; Brian Wagner; John C Ringold; Mohamed G Sayed; Abul F Ahmed; Patrick M Lynch; Christopher I Amos; Pertti Sistonen; Lauri A Aaltonen

doi:10.1086/340258

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Common Deletion of SMAD4 in Juvenile Polyposis Is a Mutational Hotspot

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Common Deletion of SMAD4 in Juvenile Polyposis Is a Mutational Hotspot

James R Howe, Jason Shellnut, Brian Wagner, John C Ringold, Mohamed G Sayed, Abul F Ahmed, Patrick M Lynch, Christopher I Amos, Pertti Sistonen and Lauri A Aaltonen

American journal of human genetics, Vol.70(5), pp.1357-1362

05/2002

DOI: 10.1086/340258

PMCID: PMC447611

PMID: 11920286

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Abstract

Juvenile polyposis (JP) is an autosomal dominant syndrome in which affected patients develop upper- and/or lower-gastrointestinal (GI) polyps. A subset of families with JP have germline mutations in the SMAD4 ( MADH4 ) gene and are at increased risk of GI cancers. To date, six families with JP have been described as having the same SMAD4 deletion (1244–1247delAGAC). The objective of the present study is to determine whether this deletion is a common ancestral mutation or a mutational hotspot. DNA from members of four families with JP, from Iowa, Mississippi, Texas, and Finland, that had this 4-bp deletion was used to genotype 15 simple tandem repeat polymorphism (STRP) markers flanking the SMAD4 gene, including 2 new STRPs within 6.3 and 70.9 kb of the deletion. Haplotypes cosegregating with JP in each family were constructed, and the distances of the closest markers were determined from the draft sequence of the human genome. No common haplotype was observed in these four families with JP. A 14-bp region containing the deletion had four direct repeats and one inverted repeat. Because no common ancestor was suggested by haplotype analysis and the sequence flanking the deletion contains repeats frequently associated with microdeletions, this common SMAD4 deletion in JP most likely represents a mutational hotspot.

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Title: Subtitle: Common Deletion of SMAD4 in Juvenile Polyposis Is a Mutational Hotspot
Creators: James R Howe - Department of Surgery, University of Iowa College of Medicine, Iowa City, IA; Departments of
Jason Shellnut - Department of Surgery, University of Iowa College of Medicine, Iowa City, IA; Departments of
Brian Wagner - Department of Surgery, University of Iowa College of Medicine, Iowa City, IA; Departments of
John C Ringold - Department of Surgery, University of Iowa College of Medicine, Iowa City, IA; Departments of
Mohamed G Sayed - Department of Surgery, University of Iowa College of Medicine, Iowa City, IA; Departments of
Abul F Ahmed - Department of Surgery, University of Iowa College of Medicine, Iowa City, IA; Departments of
Patrick M Lynch - Department of Surgery, University of Iowa College of Medicine, Iowa City, IA; Departments of
Christopher I Amos - Department of Surgery, University of Iowa College of Medicine, Iowa City, IA; Departments of
Pertti Sistonen - Department of Surgery, University of Iowa College of Medicine, Iowa City, IA; Departments of
Lauri A Aaltonen - Department of Surgery, University of Iowa College of Medicine, Iowa City, IA; Departments of
Resource Type: Journal article
Publication Details: American journal of human genetics, Vol.70(5), pp.1357-1362
Publisher: The American Society of Human Genetics
DOI: 10.1086/340258
PMID: 11920286
PMCID: PMC447611
ISSN: 0002-9297
eISSN: 1537-6605
Alternative title: Common SMAD4 Deletion in JP
Language: English
Date published: 05/2002
Academic Unit: Surgery
Record Identifier: 9984051577202771

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