Etiologie van spina bifida in geselecteerde muizenmutanten met fenotypes die sterk de menselijke situatie benaderen
03 / 2003 - 09 / 2006
Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO)
Neural tube closure defects (NTCDs), the best known of which are spina bifida and anencephaly, are congenital abnormalities affecting approximately 1 in 1000 human neonates. The aetiology of NTCDs is multifactorial, comprising both genetic and environmental components. Research aimed at understanding and preventing NTCDs is primarily carried out in animal models. Currently, over one hundred spontaneous and gene targeted mouse mutants displaying NTCDs exist. However, no significant genetic association has been found yet between human and mouse NTCD cases. One explanation for this is that candidate genes were screened in spina bifida cases in humans, while these genes originally emerged from exencephaly cases in mice. Furthermore, although periconceptional intake of folic acid causes a reduction in the occurrence of NTCDs, a decrease in incidence of human NTCDs below 1 in 2000 births appears not attainable. The currently employed genetic and dietary approaches are therefore far from effective. This illustrates the need for an alternative approach to identify the responsible genes and to design adequate intervention methods that prevent the development of NTCDs. Here, it is proposed that focusing on a selected group of mutant mice, the phenotypes of which closely resemble human spina bifida, will be more constructive than heaping together all forms of NTCDs. Determination of the genetic cause of the defects in these selected mutants will provide basic information on which diagnostic methods can be developed. Selection of candidate genes, once the affected genes have been mapped, will be aided by in depth analysis of the pathogenesis in these mice. Knowledge of the genes that are essential for proper neural tube closure will allow a well-founded choice of drugs and food components to be tested, aiming at reduction of the occurrence of spina bifida. These components can subsequently be implemented in dietary intervention.