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Genetic variation analysis of MLP, TFAP2A, and CSK in patients with neural tube defects
  1. R Klootwijk1,
  2. F A Hol1,
  3. M Wu2,
  4. J J H T Willemen1,
  5. P Groenen3,
  6. B Hamel1,
  7. H Straatman3,
  8. R P M Steegers-Theunissen3,4,
  9. E C M Mariman5,
  10. B Franke1
  1. 1Department of Human Genetics, University Medical Centre Nijmegen, PO Box 9101, 6500 HB Nijmegen, The Netherlands
  2. 2Howard Hughes Medical Institute, Center for Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
  3. 3Department of Epidemiology and Biostatistics, University Medical Centre Nijmegen, PO Box 9101, 6500 HB Nijmegen, The Netherlands
  4. 4Department of Gynaecology and Obstetrics, University Medical Centre Nijmegen, PO Box 9101, 6500 HB Nijmegen, The Netherlands
  5. 5Department of Human Biology, Maastricht University, PO Box 616, 6200 MD Maastricht, The Netherlands
  1. Correspondence to:
 Dr B Franke, Department of Human Genetics, University Medical Centre Nijmegen, PO Box 9101, 6500 HB Nijmegen, The Netherlands; 
 b.franke{at}antrg.umcn.nl

https://doi.org/10.1136/jmg.40.4.e43

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    Neural tube defects (NTDs) are congenital malformations which arise from incomplete closure of the neural tube during early embryogenesis. The most common types found in humans are spina bifida and anencephaly. These can occur together in a single family and in some cases even in one person.1

    About 70–80% of all human NTDs show complex or multifactorial inheritance patterns, indicating that both genetic and environmental factors play a part in the aetiology of this malformation.2 Folic acid supplementation reduces the incidence of human and mouse NTDs.3–7 Furthermore, supplementation of myo-inositol reduces the incidence of NTDs substantially in the NTD mouse model, curly tail.8

    In curly tail embryos, supplementary myo-inositol increases the flux through the inositol/lipid cycle, stimulating protein kinase C (Pkc) activity. Protein kinase C phosphorylates and thus activates several proteins that are directly involved in the formation of the neural tube, such as Ap2-α and Mlp (fig 1).9,10Ap2-α null as well as heterozygous and chimeric knockout mice have exencephaly.11–13Mlp knockout mice have exencephaly and spina bifida.14,15

    Figure 1

    Signal transduction relations between the proteins TFAP2A, MLP, and CSK. PTK, protein tyrosine kinase receptor; DAG, diacylglycerol; PLC, phospholipase C; PIP2, phosphatidylinositol 4,5-biphosphate; IP3, inositol 1,4,5-triphosphate; PKC, protein kinase C; SRC, Src related protein tyrosine kinases.

    Apart from the genes involved in inositol signalling, NTDs also occur in mice deficient for the Csk gene.16 This gene encodes a negative regulator of Src family tyrosine kinases and acts through phosphorylation of the Src family members at their C-terminal tyrosine residue (fig 1).17 Csk is involved in the organisation of the cytoskeleton.18

    Key points

    • In this paper, we present the results of an extensive mutation analysis in the genes coding for TFAP2A, …

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