【摘 要】
：
先天性唇腭裂(Cleft with or without palate,CL/P)是一种常见的生理缺陷,发病率为1∶500-1∶2500,临床表现为唇裂伴有或者不伴有腭裂.唇腭裂具有高度的遗传异质性,可分为综合征型和非综合征型两种类型.其中非综合征型唇腭裂受基因和环境两种因素共同影响,致病基因及分子病理机制尚不清楚.本研究收集了一个四代遗传的非综合征型唇腭裂家系,该家系共有6位患者,其中有2位表现
【机 构】
：
华中科技大学分子生物物理教育部重点实验室和生命科学与技术学院,武汉,430074 新乡医学院,基础
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先天性唇腭裂(Cleft with or without palate,CL/P)是一种常见的生理缺陷,发病率为1∶500-1∶2500,临床表现为唇裂伴有或者不伴有腭裂.唇腭裂具有高度的遗传异质性,可分为综合征型和非综合征型两种类型.其中非综合征型唇腭裂受基因和环境两种因素共同影响,致病基因及分子病理机制尚不清楚.本研究收集了一个四代遗传的非综合征型唇腭裂家系,该家系共有6位患者,其中有2位表现为双侧唇裂,3位表现为单侧唇裂,1位表现为双侧唇裂伴腭裂,遗传方式为常染色体显性并伴有外显不全现象.通过对该家系两位患者的外显子组测序结果分析,我们鉴定了CDH1基因上的一个新发突变c.G468C(p.Trp156Cys),Sanger测序验证发现该突变在家系内与唇腭裂的疾病表型共分离,此外在107个正常人中不存在该突变. CDH1基因编码一种钙依赖性细胞粘附蛋白E-cadherin,是重要的细胞粘附受体,并且在腭板融合时的腭上皮细胞中高表达,对保持上皮细胞顶-基底极性有重要作用.大量研究报道CDH1基因突变与胃癌和乳腺浸润性小叶癌相关联,该基因作为一个癌症易感基因首次与唇腭裂关联是在遗传性弥漫性胃癌患者中发现,然而在本研究的家系中,患者除了唇腭裂之外目前尚无癌症表型.但是,对于该基因突变引起的临床异质性的原因尚不清楚,表型异质性一般与基因突变的位置及性质有关.已有研究证实CDH1基因此位点色基酸(Trp 156,W)突变为丙氨酸(Ala156,A)时会影响该蛋白的二聚体的形成,该蛋白的二聚体形式对于细胞粘附具有重要作用.由此推测,本家系中鉴定到的突变p.Trp156Cys可能也会对蛋白二聚体的形成产生影响,进而影响蛋白质的正常功能.关于该基因突变引起唇腭裂的分子机制还不清楚,该突变是否是通过影响蛋白二聚体的形成,进一步对细胞间粘附作用产生影响,从而导致发育中的唇和腭不能正常闭合有待深入的研究.
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