A novel mutation, Ala315Ser, in FGFR2: a gene-environment interaction leading to craniosynostosis?
A novel mutation, Ala315Ser, in FGFR2: a gene-environment interaction leading to craniosynostosis?
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DOI：
10.1038/sj.ejhg.5200499
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发表时间：
2000-08-01
影响因子：
5.2
通讯作者：
Wilkie, AOM
中科院分区：
文献类型：
--
作者：
Johnson, D;Wall, SA;Wilkie, AOM
成纤维细胞生长因子受体1、2和3(FGFR1、-2和-3)和TWIST基因的突变已在几种形式的颅突融合中被发现。然而，仍然有相当数量的非综合征性颅缝早闭患者无法确定遗传原因。我们描述了一种新的FGFR2杂合突变(943G-->；T，编码氨基酸替代Ala315Ser)，该突变发生在一名患有非综合征型单冠状颅缝早闭的女孩身上。这种突变也存在于她的母亲和她的外祖父身上，他们有轻微的面部不对称，但没有颅缝融合。这些人都没有典型的与FGFR2突变有关的Crouzonid外观。然而，产科病史显示，先证者在宫内持续臀位，并通过剖腹产分娩，当时颅骨受到明显压缩。我们认为，这种特殊的FGFR2突变只会增加颅缝融合的易感性，并且额外的环境伤害(在这种情况下，与臀位相关的胎头约束)是颅缝融合发生所必需的。据我们所知，这是首次报道弱致病性突变和宫内约束之间的相互作用，导致颅突融合。
Mutations in the fibroblast growth factor receptor 1, 2 and 3 (FGFR1, -2 and -3) and TWIST genes have been identified in several syndromic forms of craniosynostosis. There remains, however, a significant number of patients with non-syndromic craniosynostosis in whom no genetic cause can be identified. We describe a novel heterozygous mutation of FGFR2 (943G --> T, encoding the amino acid substitution Ala315Ser) in a girl with non-syndromic unicoronal craniosynostosis. The mutation is also present in her mother and her maternal grandfather who have mild facial asymmetry but do not have craniosynostosis. None of these individuals has the Crouzonoid appearance typically associated with FGFR2 mutations. However, the obstetric history revealed that the proband was in persistent breech presentation in utero and was delivered by Caesarean section, at which time compression of the skull was apparent. We propose that this particular FGFR2 mutation only confers a predisposition to craniosynostosis and that an additional environmental insult (in this case foetal head constraint associated with breech position) is necessary for craniosynostosis to occur. To our knowledge, this is the first report of an interaction between a weakly pathogenic mutation and intrauterine constraint, leading to craniosynostosis.