Pleiotropic skeletal and ocular phenotypes of the mouse mutation congenital hydrocephalus (ch/Mf1) arise from a winged helix forkhead transcription factor gene
Pleiotropic skeletal and ocular phenotypes of the mouse mutation congenital hydrocephalus (ch/Mf1) arise from a winged helix forkhead transcription factor gene
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DOI：
10.1093/hmg/8.4.625
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发表时间：
1999-04-01
影响因子：
3.5
通讯作者：
Chakravarti, A
中科院分区：
文献类型：
--
作者：
Hong, HK;Lass, JH;Chakravarti, A
先天性脑积水是一种病因多样、知之甚少但相对常见的出生缺陷，大多数人类病例为散发性，具有家族性，表现出相当大的表型和病因异质性。我们研究了常染色体隐性遗传突变小鼠先天性脑积水（ch），以确定候选人的人类脑积水基因及其修饰，ch小鼠具有先天性，致死性脑积水与多种发育缺陷，特别是骨骼缺陷，在组织来源于头神经嵴。我们利用定位克隆的方法来映射在D13Mit294附近的CH，并确认CH表型是由编码有翼螺旋/叉头转录因子（Mf1）的基因中的无义突变的纯合性引起的。基于连锁遗传标记，我们进行了详细的表型突变纯合子和杂合子的表征，以证明突变基因的多效性效应。令人惊讶的是，ch杂合子具有类似于Axeneir-Rieger异常的多发性眼前节缺陷的与青光眼相关的独特表型。我们还定位了该基因家族的第二个成员（Hfh1），其是其他发育缺陷的候选者，类似于Mf1近端的470 kb。
Congenital hydrocephalus is an etiologically diverse, poorly understood, but relatively common birth defect, Most human cases are sporadic with familial forms showing considerable phenotypic and etiologic heterogeneity. We have studied the autosomal recessive mouse mutation congenital hydrocephalus (ch) to identify candidate human hydrocephalus genes and their modifiers, ch mice have a congenital, lethal hydrocephalus in association with multiple developmental defects, notably skeletal defects, in tissues derived from the cephalic neural crest. We utilized positional cloning methods to map ch in the vicinity of D13Mit294 and confirm that the ch phenotype is caused by homozygosity for a nonsense mutation in a gene encoding a winged helix/forkhead transcription factor (Mf1). Based on linked genetic markers, we performed detailed phenotypic characterization of mutant homozygotes and heterozygotes to demonstrate the pleiotropic effects of the mutant gene. Surprisingly, ch heterozygotes have the glaucoma-related distinct phenotype of multiple anterior segment defects resembling Axenfeld-Rieger anomaly, We also localized a second member of this gene family (Hfh1), a candidate for other developmental defects, similar to 470 kb proximal to Mf1.