Identification of Sonic hedgehog as a candidate gene responsible for holoprosencephaly
Identification of Sonic hedgehog as a candidate gene responsible for holoprosencephaly
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DOI：
10.1038/ng1196-353
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发表时间：
1996-11-01
期刊：
影响因子：
30.8
通讯作者：
Scherer, SW
中科院分区：
文献类型：
--
作者：
Belloni, E;Muenke, M;Scherer, SW
前脑无裂畸形（HPE）是一种遗传和表型异质性疾病，涉及前脑和中面的发育，其发病率为1：16，000活产婴儿和1：250人工流产1。这种疾病与几种不同的面容和表型变异有关：在最极端的情况下，无眼症或独眼症是明显的，沿着先天性缺乏成熟的鼻子。不太严重的形式的特征是面部畸形，其特征是眼距过宽，上唇和/或鼻子的缺陷，以及嗅觉神经或胼胝体的缺失。已经描述了几种涉及大脑和面部的中间表型。其中一个基因位点HPE 3定位于7号染色体的末端带。我们已经进行了广泛的物理作图研究，建立了HPE 3的临界区间，随后确定了音刺猬（SHH）基因作为该疾病的主要候选基因，SHH位于与HPE相关的染色体重排的15-250个碱基（kb）范围内，这表明“位置效应”在HPE的病因学中具有重要作用。如随附报告中所详述，SHH的这种作用通过检测遗传性HPE患者的点突变得到证实2。
Holoprosencephaly (HPE) is a genetically and phenotypically heterogenous disorder involving the development of forebrain and midface, with an incidence of 1:16,000 live born and 1:250 induced abortions1. This disorder is associated with several distinct facies and phenotypic variability: in the most extreme cases, anophthalmia or cyclopia is evident along with a congenital absence of the mature nose. The less severe form features facial dysmorphia characterized by ocular hypertelorism, defects of the upper lip and/or nose, and absence of the olfactory nerves or corpus callosum. Several intermediate phenotypes involving both the brain and face have been described. One of the gene loci,HPE3, maps to the terminal band of chromosome 7. We have performed extensive physical mapping studies and established a critical interval forHPE3, and subsequently identified the sonic hedgehog (SHH) gene as the prime candidate for the disorder.SHHlies within 15–250 kilobases (kb) of chromosomal rearrangements associated with HPE, suggesting that a ‘position effect’ has an important role in the aetiology of HPE. As detailed in the accompanying report, this role for SHH is confirmed by the detection of point mutations in hereditary HPE patients2.