报告题目：Embryonic Consequences of Abnormal Folate Transport During Development
报告人：Richard H. Finnell 教授
主持人：冯新华 教授
时 间：2017年8月15日（周二）下午4点
地 点：纳米楼457报告厅
报告人简介：
Richard H. Finnell教授现任美国贝勒医学院分子细胞生物学系与医学系资深研究员、上海交通大学医学遗传学研究所兼职教授、华东师范大学生命科学学院兼职教授、北京大学公共健康学院兼职教授等。
Finnell教授1975年获美国俄勒冈大学人类学学士学位、1978年获英属哥伦比亚大学医学遗传学硕士学位、1980年获俄勒冈大学医学遗传学博士学位。作为一名儿科遗传学家，Finnell教授一直致力于研究环境因素引起出生缺陷的遗传易感性，应用干细胞技术检测引起出生缺陷的潜在致畸物，通过建立小鼠模型了解出生缺陷的发病机制，并利用高度创新的方法来治疗这些缺陷。
Finnell教授现已发表了300多篇论文，包括Science、Nature Genetics、Nature Cell Biology、PNAS和Development Cell等国际知名期刊。
讲座摘要：
The presentation will cover two disorders linked to the human folate receptor alpha. The first portion of the presentation will focus on the role of preconceptional folic acid supplementation in reducing the occurrence of complex congenital defects in humans. Specifically we will focus on the role of folic acid in the prevention of neural tube defects. To better understand the mechanisms underlying theses beneficial effects, we developed a variety of genetically modified mice whose folate transport systems have been ablated. Administration of exogenous one-carbon sources partially rescues the nullizygous embryos; although they present with a low prevalence of malformations involving the neural tube, craniofacies, heart, eyes and abdominal wall. Inadequate maternal folate causes notable changes in the Forl1 mutant embryos at the molecular and cellular levels, clearly indicating the importance of folate homeostasis during early mammalian development.
Given the importance of maintaining folate homeostasis during development, we performed translational research in human cohorts of complex birth defects, focusing on those mechanisms and gene variants identified in the mouse model systems. We observed a post-translational modification of target proteins at lysine residues when cellular homocysteine (Hcy) levels are elevated. This process, known as homocysteinylation, results in protein malfunction and/or neoantigen formation. The latter triggers an complement activation, and inflammatory responses. The level of protein homocysteinylation in vivo is directly correlated with plasma Hcy, which is elevated in situations of low dietary folic acid, or when folic acid metabolism/transport is disturbed, as is the case with the genetically susceptible individuals. A variety of environmental stimuli, including smoking, heavy metals, and alcohol increase homocysteinylation. Such environmental contaminants are known to occur in regions with endemically high prevalence rates of birth defects.
The second part of the talk will focus on the cerebral folate deficiency (CFD) syndrome, which is characterized by very low concentration of 5-methyltetrahydrofolate (5-MTHF) in cerebrospinal fluid, while folate levels in plasma and red blood cells are normal. CFD patients present with symptoms including: developmental delay, ataxia, dyskinesias, spasticity, speech difficulties and epilepsy. Previously, mutations in several folate pathway genes, including hFR (folate receptor alpha), DHFR (dihydrofolate reductase), PCFT (proton coupled folate transporter) and MTHFS (methenyltetrahydrofolate synthetase) have been identified in CFD patients. In an effort to identify causal mutations for CFD, we performed whole exome sequencing analysis of DNA samples collected from a CFD patient, her healthy sibling, and her biological parents. A de novo mutation in human Capicua gene (CIC), c.1057C>T (p.R353X), was identified in the patient. A second CFD patient was confirmed as a compound heterozygote of two splice site variants of CIC gene, IVS1360+32G>AG and IVS3796-15C>CT. In addition, a missense mutation predicted to be damaging, c.1738G>GT (p.G580GC) was identified in a 3rd CFD patient, as well as her healthy sibling and her father. The CIC protein is a HMG-box transcriptional repressor. The mutation identified in the CFD patient, p.R353X, yields a truncated protein which still contains the DNA binding domain (HMG box), therefore it is still able to bind to its targets, which have been found in the promoter regions of folate transport genes FOLR1, PCFT, RFC1, and DHFR, which is involved in folate metabolism. This linkage between CIC and folate transport represents a novel observation based on a fortuitous clinical finding.
