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A family with two consecutive nonsense mutations in BMPR1A causing juvenile polyposis

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Abstract

We describe a novel germline mutation of BMPR1A in a family with juvenile polyposis and colon cancer. This mutation consists of two consecutive substitutions (735–6 TG>AT) that cause two nonsense mutations (Y245X, G246X), inherited in an autosomal dominant fashion, on one parental chromosome. This mutation caused protein truncation, and represents a novel case of consecutive nonsense mutations in human disease.

Introduction

Juvenile polyposis (OMIM #174900) is an autosomal dominant condition in which affected individuals develop hamartomatous polyps of the colon, rectum, and less frequently, the stomach [1]. Juvenile polyposis patients are at significant risk for developing gastrointestinal cancer[2], [3], and some may also have hereditary hemorrhagic telangiectasia [4], [5].

Two predisposing genes have been identified in juvenile polyposis: SMAD4 located at 18q21 [6], [7] and BMPR1A at 10q22∼q23 [8]. Both genes are members of the transforming growth factor beta superfamily, and mutations of the coding sequence of each gene have been found in ∼20% of juvenile polyposis cases [9]. Approximately one half of the germline mutations thus far described have been microdeletions, the remainder being substitutions.

Here, we describe the novel finding of two consecutive substitutions leading to two consecutive nonsense codons in a family with juvenile polyposis.

Section snippets

Clinical report

The proband (II-3, Fig. 1) developed lower gastrointestinal bleeding at age 5, and six hamartomatous polyps were removed upon sigmoidoscopy. Over the following 18 years of surveillance, 107 polyps were removed, all of them hamartomatous without adenomatous features. At age 21, the proband was found to have gastric polyps. The proband's mother (I-2) had a negative colonoscopy at age 42 and was still healthy at age 59 and without symptoms. His father (I-1) was deemed to be healthy, but died at

Results

Blood samples were obtained from individuals II-2, III-1, III-2, and III-3. DNA was extracted, and individual II-2 was sequenced for all exons and intron–exon boundaries of SMAD4 and BMPR1A. Two substitutions were found in consecutive nucleotides of exon 7 of BMPR1A (Fig. 2a), 735–6 TG>AT. Notably, each of these substitutions would change the corresponding amino acid into a stop codon (Y245X, G246X). Individual III-1 also had this mutation (and had no known polyps at age 20), as did III-3 (who

Discussion

There have been several reports of two consecutive substitutions and missense mutations in human disease genes. Van Belzen et al. [10] described a Dutch family with ataxia telangiectasia (autosomal recessive) in which an affected brother and sister were both homozygous for two consecutive substitutions in exon 55 of the ATM gene, leading to two consecutive missense mutations (D2625E, A2626P). Mullan et al. [11] found substitutions in families with early-onset Alzheimer disease that created

Acknowledgments

Thanks go to Victor McKusick at Johns Hopkins University and Peter Stenson at the Human Genome Mutation Database for their help in searching for similar cases of mutation. This study was funded by NIH grant 5R01-09813-03 and the Roy J. Carver Charitable Trust.

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