l.Construct a multidisciplinary European research consortium capable of leading an international search for the genes responsible for predisposition to spina bifida and anencephaly;
2.Positionally clone genes associated with NTD as a monogenic trait in humans;
3.Assemble a large series of sporadic and familial NTD cases in which to study genes identified as being of importance in the murine model;
4.Carry out a mutagenesis screen in the mouse to identify new "NTD" genes;
5.Investigate the interaction between established NTD genes in the mouse;
6.Develop analytic strategies for dealing with the data analysis in complex traits using NTD as a basis;
7. Study environmental causes of NTD:
a) Investigate the role of genetic factors in the association between folate metabolism and NTD using the mouse models;
b) Carry out a retrospective and prospective review of neural tube defects and associated malformations in the offspring of women treated with the anticonvulsant sodium valproate in order to assemble a study group in which to evaluate the relationship between genotype, biochemical phenotype and predisposition to malformation Neural Tube defects (N'IDs) are a common group of malformations involving defective formation of the brain and spinal cord.
Anencephaly and spina bifida are the best-recognised examples. Marked variation in place and time, and association with dietary folate deficiency and specific teratogens such as anticonvulsant sodium valproate point to environmental causative factors. The description of a growing number of major NTD genes in the mouse, occasional monogenic human NTD syndromes and the significant excess in close relatives provide clear evidence in favour of a genetic component among the causative mechanisms. The INTEGER project will unite the multidisciplinary resources of the European Union in the search for these genes.
Their discovery will be a major step towards completion of the Human Genome Project; the rapid progress towards identification of simple monogenic genedefects exposes our lack of understanding of complex disorders such as birth defects. Discovery of the genes associated with abnormal development provides access to the developmental pathways of the normal human nervous system. Birth defects are a major health burden affecting 1 in 30 babies. NTDs are among the most common, varying from 1 in 3000 to more than 1 in 300 in recent studies in high-risk areas of Europe. The wide availability of obstetric ultrasound and therapeutic termination has served to obscure the prevalence of NTDs but has not diminished the psychological cost to more than 5,000 couples in the EU each year.
An understanding of the genetic basis of predisposition to this group of congenital anomalies will open the way to more effective targeting of preventive strategies. The INTEGER project brings together four major laboratory teams interested in NTDs in mouse and Man with a network of clinicians, epidemiologists and statistical geneticists. Two genes responsible for rare forms of monogenic NTD will be cloned and a large clinical resource established in which to investigate mutations in candidate genes. Several genes are recognised in the mouse as causing NTDs. As these are investigated, the murine research groups will screen the mouse genome for new NTD genes and explore their interaction with each other and with known environmental factors. Gene environment interaction in humans will be approached by the study of impaired folate metabolism and predisposition to malformation in pregnancies exposed to the anticonvulsant sodium evaporate.
Funding SchemeCSC - Cost-sharing contracts
WC1N 1EH London