Carrasquillo Minerva M, McCallion Andrew S, Puffenberger Erik G, Kashuk Carl S, Nouri Nassim, Chakravarti Aravinda
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, 600 N. Wolfe St., Jefferson St. Bldg., 2-109, Baltimore, Maryland 21287, USA.
Nat Genet. 2002 Oct;32(2):237-44. doi: 10.1038/ng998. Epub 2002 Sep 23.
Genetic studies of Hirschsprung disease, a common congenital malformation, have identified eight genes with mutations that can be associated with this condition. Mutations at individual loci are, however, neither necessary nor sufficient to cause clinical disease. We conducted a genome-wide association study in 43 Mennonite family trios using 2,083 microsatellites and single-nucleotide polymorphisms and a new multipoint linkage disequilibrium method that searches for association arising from common ancestry. We identified susceptibility loci at 10q11, 13q22 and 16q23; the gene at 13q22 is EDNRB, encoding a G protein-coupled receptor (GPCR) and the gene at 10q11 is RET, encoding a receptor tyrosine kinase (RTK). Statistically significant joint transmission of RET and EDNRB alleles in affected individuals and non-complementation of aganglionosis in mouse intercrosses between Ret null and the Ednrb hypomorphic piebald allele are suggestive of epistasis between EDNRB and RET. Thus, genetic interaction between mutations in RET and EDNRB is an underlying mechanism for this complex disorder.
先天性巨结肠症是一种常见的先天性畸形，对其进行的遗传学研究已确定了八个携带与该病症相关突变的基因。然而，单个位点的突变对于引发临床疾病既非必要条件也非充分条件。我们在43个门诺派家庭三联体中开展了一项全基因组关联研究，使用了2083个微卫星和单核苷酸多态性，以及一种新的多点连锁不平衡方法，该方法用于寻找由共同祖先引发的关联性。我们在10q11、13q22和16q23处确定了易感位点；位于13q22的基因是EDNRB，编码一种G蛋白偶联受体（GPCR），位于10q11的基因是RET，编码一种受体酪氨酸激酶（RTK）。在患病个体中RET和EDNRB等位基因具有统计学意义的联合传递，以及在Ret基因敲除小鼠与Ednrb基因低表达花斑等位基因小鼠的杂交后代中神经节缺乏的互补性缺失，提示了EDNRB与RET之间存在上位效应。因此，RET和EDNRB突变之间的基因相互作用是这种复杂疾病的潜在机制。
