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dc.contributor.author姜煜
dc.contributor.author郭东炜
dc.contributor.author郭奕斌
dc.date.accessioned2018-11-26T08:58:39Z
dc.date.available2018-11-26T08:58:39Z
dc.date.issued2017
dc.identifier.citation分子诊断与治疗杂志,2017,(4)
dc.identifier.issn1674-6929
dc.identifier.urihttps://dspace.xmu.edu.cn/handle/2288/166101
dc.description.abstract致死性侏儒症(thanatophoric dysplasia,TD)是重型短肢畸形病中相对常见的致死性遗传性骨病,分为TD-I和TD-II 2型,它们都是由于FGFR3基因发生致死突变所致。TD-I型存在多种致病性突变,其中以c.742C〉T/p.R248C突变最为常见。本病为常染色体显性遗传(autosomal dominant,AD),杂合突变即可致死,但为何表型、基因型正常的父母会生出带有p.R248C突变的患胎并且是纯合突变的死胎?如果是新生突变,又为何会接连数胎生出同样的患胎?p.R248C高发突变的机制是什么?本文重点围绕这些问题,从"FGFR3(Fibroblast growth factor receptor 3)基因和FGFR3受体(Fibroblast growth factor receptor 3)的结构和功能,TD-I型p.R248C高发突变的发生机制,正常父母生出纯合致死突变的可能机制"几方面进行剖析,指出:(1)FGFR3基因及其受体蛋白结构和功能的特殊性是高发突变发生的物质基础;(2)位于IgⅡ和IgⅢ结构域连接区的氨基酸是极性很强的亲水氨基酸,很容易与带电离子结合而影响α螺旋结构,故易受外来理化因素的攻击、诱变而发生改变;(3)正常父母生出纯合致死突变,推测有两种可能:一种是夫妇一方的生殖腺已带有该高发突变,当胎儿从亲代遗传了一次突变后,只需在另一位点上再发生一次新生突变即可产生;另一种是夫妇双方的生殖腺都是该突变的嵌合体,当两者结合在一起,就有可能产生纯合突变。此外,还对未来发展趋势进行了展望。本文旨在探讨c.742C〉T/p.R248C高发突变和纯合突变发生的机制,进而为其今后的诊断和防治工作提供理论依据。
dc.description.abstractThanatophoric dysplasia(TD),divided into TD type I and TD type II,is a genetic bone disease caused by the fatal mutation of FGFR3 gene.It is relatively common lethal hereditary osteopathy among severe short limb malformations.TD-I type has many kinds of pathogenic mutations,of which c.742CT/p.R248 C mutation is the most common.This disease is an autosomal dominant(AD) genetic disease which means heterozygous mutations can be lethal.However,why some parents with normal genotypes and phenotypes can give birth to a stillbirth who carried the homozygous mutation p.R248C? If it is a novel mutation,why the successive fetuses with the same mutation were born? What is the high incidence mechanism of p.R248 C mutation? This paper focus mainly around these problems,from"The structure and function of FGFR3 gene and FGFR3 receptor;The pathogenetic mechanism of high incidence of p.R248 C in TD type I;The possible mechanisms of normal parents producing homozygous lethal mutation",several aspects are analyzed and pointed out:(1)FGFR3 gene and the structure and function of its receptor protein is the material base of high frequent mutation;(2) Some amino acids,located in the connected region of Ig Ⅱ and Ig Ⅲ domain,are strong polar hydrophilic amino acids,which tend to bind charged ions to influence the alpha helical structure,therefore,it is easy to be affected by external physical and chemical factors;(3) Normal parents give birth to fetus with homozygous lethal mutation,there are 2 possibilities:one is the reproductive gonad of one of the parents has carried the hot mutation,and the fetus inherited the hot mutation,under these circumstances,as long as a same mutation happen in its allele,which will lead to the generation of homozygous mutation;another is the reproductive glands of couples are the mutant chimeras,when the two are combined together,it is possible to generate homozygous mutation.In addition,the future development trend is prospected.The purpose of this paper is to explore th
dc.description.sponsorship闽粤合作科研基金(71010025)
dc.language.isozh_CN
dc.subject致死性侏儒症I型(TD-I)
dc.subjectFGFR3基因
dc.subjectp.R248C
dc.subject高发突变
dc.subject发生机制
dc.subjectPathogenetic mechanism
dc.title致死性侏儒症Ⅰ型高发突变发生机制浅析
dc.title.alternativeAnalysis of the mechanism of high incidence of thanatophoric dysplasia type I
dc.typeArticle


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