[BIC-announce] FW: Killam Seminar - TODAY: The role of follic acid in neural tube closure defects: Case open...or closed?

[Jennifer Chew, Ms.]

PLEASE DISCARD IF THIS IS A DUPLICATE.  THANK YOU.  JENNIFER 



*****REMINDER*****

 

Dear Colleagues: 

I would like to invite you to attend the upcoming Killam Seminar on Tuesday March 18th at 4:00 pm at the de Grandpré Communications Centre of the MNI.  The speaker will be Dr. Richard Finnell, The Margaret M. Alkek Professor of Medical Genetics, Institute of Biosciences and Technology of the Texas A & M University Health Science Center, and Executive Director and President of the Texas Institute for Genomic Medicine, Houston, Texas.

Dr. Finnell's main research interest over the years has been in the field of pharmacogenomics, more specifically mechanisms of teratogenesis and genes predisposing to teratogenicity of anticonvulsant medication.  In recent years, he has focused on the relationship of various genes involving folic acid metabolism and transport to neural tube defects, as well as the role of valproic acid in teratogenesis.

Dr. Finnell is a dynamic speaker and an international expert in this field. Several  pertinent recent publications are attached.

 

A revised title and abstract of his presentation is also attached, as well as a poster which I would ask you to post.


Hoping to see you at the lecture,

Sincerely yours,

 Eva Andermann, MDCM, PhD, FCCMG
Director, Neurogenetics Unit, 
Montreal Neurological Hospital and Institute;
Professor, Departments of Neurology and Neurosurgery and
Human Genetics, 
McGill University
3801 University St., Room 127
Montreal, Quebec, Canada H3A 2B4
Tel:      514-398-8529
Fax:    514-398-1276
Email: eva.andermann at mcgill.ca <mailto:eva.andermann at mcgill.ca> 

The Role of Folic Acid in Neural Tube Closure Defects: Case Open.....or Closed?

 Richard H. Finnell, Ph.D.
Institute of Biosciences and Technology, Texas A&M University Health Science Center
Houston, USA and The Texas Institute for Genomic Medicine, Houston, USA, rfinnell at ibt.tmc.edu;

 

Periconceptional folic acid supplementation is generally believed to be protective and serves to reduce the occurrence of complex congenital defects in humans.  In an effort to understand the mechanisms underlying the beneficial effects of folic acid during development, we have developed genetically modified mice whose folate transport systems have been ablated.  Inactivation of the folate binding protein-1 (Folr1) gene results in embryonic lethality by E10. Administration of folinic acid to Folr1 deficient dams rescues the nullizygous embryos; however, surviving embryos present with malformations involving the neural tube, craniofacies, heart, eyes and abdominal wall.   In the absence of adequate maternal folate, there are notable changes in the For11 mutant embryos at both the molecular and cellular levels.  Similar results were obtained when we inactivated the reduced folate carrier gene (RFC-1), in that the mice were born with significant congenital defects in spite of supplementation with folic acid.  These studies clearly indicate the importance of folate homeostasis during early mammalian development.

 

Given the importance of maintaining folate homeostasis during development, the search for candidate genes that best explain NTD susceptibility were sought within the folate transport and metabolic pathways.  Although numerous studies have shown folate pathway gene variants to be risk factors for NTDs, such variants, at present, only account for a small percentage of NTD births.  As such, there remain multiple avenues to explore with respect to discerning the principal mechanisms underlying the beneficial consequences of folate supplementation in the periconceptional period.  One possibility involves the homocysteinylation of target proteins at lysine residues when cellular homocysteine (Hcy) levels are elevated.  This is a process whereby Hcy covalently binds to lysine residues on proteins resulting in protein malfunction (direct damage) and/or neoantigen formation. Formation of neoantigens triggers an autoimmune process, complement activation, and inflammation (indirect damage). 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. Evidence in support of this hypothesis will be discussed. 

 

Finally, despite the fact that the preventative effects of folic acid on neural tube defect risk are well established, there remain significant populations of women who took folic acid during pregnancy and still had NTD-compromised pregnancies.  Thus, as substantial population burden still exists. Considering other nutritional factors, it appears as if low levels of vitamin B12, independent of folate, are associated with increased risk for an NTD pregnancy.  Other nutrients such as methionine, zinc, vitamin C and choline are also suspected of modifying the NTD risk. We have taken advantage of a mid-gestational serum bank linked to pregnancy outcome to examine a number of nutrient analytes for their potential role as risk factors in NTDs.  The results confirm that nutrients other than folic acid are critical for normal embryogenesis.

 

The impact of folic acid on embryonic development is irrefutable.  But whether or not it is the best intervention strategy to prevent complex birth defects remains to be determined.