Howe James R, Shellnut Jason, Wagner Brian, Ringold John C, Sayed Mohamed G, Ahmed Abul F, Lynch Patrick M, Amos Christopher I, Sistonen Pertti, Aaltonen Lauri A
Department of Surgery, University of Iowa College of Medicine, Iowa City, IA 52242-1086, USA.
Am J Hum Genet. 2002 May;70(5):1357-62. doi: 10.1086/340258. Epub 2002 Mar 27.
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.
青少年息肉病（JP）是一种常染色体显性综合征，患病患者会在上消化道和/或下消化道（GI）出现息肉。一部分患有JP的家族在SMAD4（MADH4）基因中存在种系突变，患GI癌症的风险增加。迄今为止，已有六个患有JP的家族被描述为具有相同的SMAD4缺失（1244 - 1247delAGAC）。本研究的目的是确定这种缺失是常见的祖先突变还是突变热点。来自爱荷华州、密西西比州、德克萨斯州和芬兰的四个患有JP且有这种4碱基对缺失的家族成员的DNA，用于对SMAD4基因侧翼的15个简单串联重复多态性（STRP）标记进行基因分型，包括在缺失位点6.3和70.9 kb范围内的2个新的STRP。构建了每个家族中与JP共分离的单倍型，并根据人类基因组草图序列确定了最接近标记的距离。在这四个患有JP的家族中未观察到共同的单倍型。包含该缺失的一个14碱基对区域有四个直接重复和一个反向重复。由于单倍型分析未提示共同祖先，且缺失侧翼序列包含经常与微缺失相关的重复序列，因此JP中这种常见的SMAD4缺失很可能代表一个突变热点。
