对一对双胞胎与镜像裂唇的多原子分析确定了FGF20的致病变体,该变体是由ZFP57上游的微分甲基化修饰的
Waheed Awotoye1, Ligiane A Machado-Paula1, Luke Hovey1
1College of Dentistry and Dental Clinics, University of Iowa, Iowa City, IA, 52240.
medRxiv : the preprint server for health sciences
|November 28, 2024
概括
非综合性裂唇 (nsCL) 涉及遗传变异和DNA甲基化,可能解释其左侧流行. 这项研究在双胞胎对中探索了这些因素,为 orofacial clefts (OFCs) 的发展和预防提供了见解.
科学领域:
- 遗传学和发育生物学
- 表观遗传学和基因调控
- 头骨面部发育和出生缺陷
背景情况:
- 耳面裂 (OFCs) 是常见的出生缺陷,源于面形态发生障碍.
- 无综合症裂唇 (nsCL) 呈现出非随机的左侧横向性,影响左侧的频率是右侧的两倍.
- 调查导致nsCL病因和横向性的遗传和表观遗传因素至关重要.
研究的目的:
- 识别与非综合征裂唇 (nsCL) 和其横向性相关的遗传变异和DNA甲基化模式.
- 研究纤维细胞生长因子20 (FGF20) 和指转录因子57 (ZFP57) 在nsCL中的作用.
- 探索OFC发展中的遗传倾向和表观遗传修饰之间的相互作用.
主要方法:
- 全基因组测序 (WGS) 在一对单胞胎双胞胎身上进行了镜像nsCL,他们的母亲和不受影响的父亲.
- 进行了DNA-甲基组分析,以确定镜子双胞胎之间的差异甲基化区域 (DMR).
- 在单边裂唇病例的独立队列上的复制分析验证了已识别的DMR.
主要成果:
- 在FGF20 (p.Ile79Val) 中发现了一种蛋白质改变变异,与家族中的nsCL分离.
- 在ZFP57上游的差异甲基化区域 (DMR) 在一个独立的队列中被确定并确认.
- 富化分析揭示了DMRs参与早期胚胎DNA甲基化,其中一个作为TFAP2A结合位;ZFP57可能在左/右轴规范中发挥作用.
结论:
- 这项研究表明,在确定nsCL横向性时,病原性变异 (例如,在FGF20中) 和DNA甲基化 (例如,在ZFP57的上游) 之间的相互作用.
- 这些发现阐明了OFC开发背后的复杂机制,突出了ZFP57在左/右轴规范中的重要性.
- 了解这些因素可能会导致OFC预防和管理的新战略.
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