Wednesday, 14 September 2016 13:00

Nijmegen breakage syndrome: signaling pathway for microcephaly discovered Featured

The Hebrew University in Jerusalem, headed by Prof. Michal Goldberg and Prof. Nissim Benvenisty together with researchers from Heinrich Heine University in Dusseldorf, headed by Prof. James Adjaye, have uncovered a signalling pathway mechanism which is responsible for the formation of microcephaly. This disease picture is one of several that may occur in the genetic Nijmegen breakage syndrome (NBS).

NBS is a rare, congenital disease in which the DNA repair mechanism of the cells is disturbed. It may, inter alia, come to a chromosome fragility. Symptoms range from microcephaly over malformations of the brain and head, mental development disorders, immune sufficiency to malignant tumor building in an early childhood or juvenile stage of development. Genetic background is a mutation on chromosome no. 8 at NBS gene 1, resulting in a nibrin mutation (1,2). The role of the protein nibrin in the repair mechanism can be found here (3).

Until now it was not known how the NBS1 gene affects the brain development.

To create their in vitro model, the scientists used fibroblasts (cells of the connective tissue) from patients suffering from NBS. With his cells they created induced pluripotent stem cells (iPS). They developed the iPS cells into nerve progenitor cells. All cells carried the NBS1 gene mutation.

The researchers found out that p53 is an important target molecule of the signalling pathway of the NBS1 gene. The signal transduction of this gene leads to a reduced cell division and thus to a slower growth of cells and tissues. They also observed an inhibition of the apoptosis function (programmed cell death), through which the body can get rid of abnormal cells. The protein p53 plays an important role in this mechanism. Normally, the amount of p53 protein is regulated through a series of kinase activations.

The researchers observed different expressions of genes, which are responsible for the cell cycle. Striking many cells were in the stage of G2/M, the so-called damage checkpoint.

The differentiation of iPS cells into nerve precursor cells was also impaired. This can lead to delayed development of the brain and thus to microcephaly. The researchers concluded that all this has to do with the mutation of the NBS1 gene associated with an inability to produce sufficient quantities of protein p53.

Original publication:
Tomer Halevy, Shira Akov, Martina Bohndorf, Barbara Mlody, James Adjaye, Nissim Benvenisty & Michal Goldberg (2016): Chromosomal Instability and Molecular Defects in Induced Pluripotent Stem Cells from Nijmegen Breakage Syndrome Patients. Cell Reports 16: 1-13.

For more information about Prof. James Adjaye:


Further information: