Bidaud C, Salomon R, Edery P, Van Camp G, Pelet A, Bonduelle M, Nihoul-Fékété C, Willems P J, Munnich A, Lyonnet S
Unité de Recherches sur les Handicaps Génétiques de l'Enfant INSERM U-393, Département de Génétique, Hôpital des Enfants Malades, Institut Necker, Paris.
Gastroenterol Clin Biol. 1997;21(8-9):548-54.
Hirschsprung's disease is a frequent congenital malformation regarded as a multigenic neurocristopathy. Three susceptibility genes have been identified in Hirschsprung's disease, namely the RET proto-oncogene, the Glial cell line-Derived Neurotrophic Factor and the endothelin B receptor. A total of 174 probands with isolated Hirschsprung's disease (59 familial, 117 sporadic cases), and 4 patients with associated Waardenburg's syndrome and Hirschsprung's disease (1 familial, 3 sporadic cases) were screened for mutations in the coding sequence of the endothelin 3 gene. The coding sequence of the endothelin 3 gene was analyzed for point mutations, using a combination of SSCP analysis and direct DNA sequencing.
Two heterozygous mutations (A17T and A224T) were identified in two patients with isolated Hirschsprung's disease. Two homozygous truncations mutations (E55X and GC262->T) were identified in patients with the Waardenburg's syndrome/Hirschsprung's disease association.
The present data give further support to the role of the endothelin-signaling pathway in the development of neural crest-derived enteric neurons. They also suggest that either recessive and weakly penetrant dominant alleles could occur at the EDN3 locus, depending on the nature of the mutation.
先天性巨结肠是一种常见的先天性畸形，被认为是一种多基因神经嵴病。在先天性巨结肠中已鉴定出三个易感基因，即RET原癌基因、胶质细胞源性神经营养因子和内皮素B受体。对总共174例孤立性先天性巨结肠先证者（59例家族性、117例散发性病例）以及4例伴有瓦登伯格综合征和先天性巨结肠的患者（1例家族性、3例散发性病例）进行内皮素3基因编码序列突变筛查。采用单链构象多态性分析（SSCP）和直接DNA测序相结合的方法，分析内皮素3基因编码序列中的点突变。
在两名孤立性先天性巨结肠患者中鉴定出两个杂合突变（A17T和A224T）。在患有瓦登伯格综合征/先天性巨结肠综合征的患者中鉴定出两个纯合截短突变（E55X和GC262->T）。
目前的数据进一步支持了内皮素信号通路在神经嵴衍生的肠神经元发育中的作用。它们还表明，根据突变的性质，EDN3基因座可能出现隐性和弱显性等位基因。
