N° 161
9 April 2005 

Abnormal DNA damage response is the cause of neuronal defects in tumor-prone disorders.

NBS linked to degenerative disease
Nijmegen Breakage Syndrome (NBS) is a rare autosomal recessive disease characterized by microcephaly, chromosomal instability, radiosensitivity, immunodeficiency and cancer predisposition. NBS, Ataxia Telangiectasia (A-T) and AT-Like Disorder (A-TLD) constitute a sub-group of chromosome instability syndromes, which exhibit very similar clinical features, with further obligatory characteristics of cerebellar degeneration and ataxia in A-T and A-TLD patients. Cellular defects in these patients include radio-sensitivity, chromosome instability and cell cycle checkpoint defects. Although the genes responsible for Nijmegen Breakage Syndrome (NBS1), Ataxia-Telangiectasia (ATM) and AT-like disorder (MRE11) are distinct, these diseases share similar clinical and cellular characteristics, with distinct neurological anomalies. There is a missing puzzle piece in the molecular network linking these genetic disorders. Extensive molecular and cellular studies have shown that molecules encoded by these genes play a central role in DNA damage response, whose abrogation lead to more severe degenerative diseases usually characterized by cancer predisposition. Investigation of the DNA damage response is thus a major area of cancer research.

Depletion of DNA-repair molecule induces overactivation of p53 in the lab mouse
In a laboratory-based study at IARC, Dr Zhao-Qi Wang and his colleagues demonstrate that by specific gene disruption technology, the depletion of DNA double strand break repair molecule NBS1 in the mouse neural lineage results in a combination of the neurological anomalies of NBS, A-T and A-TLD due to over-activation of p53, the master tumour suppressor. They show for the first time that the neurological anomalies observed in chromosome instability syndromes NBS, A-T and A-TLD are due to abnormal DNA damage response. These laboratory findings from animal models uncover that deficiency of DNA repair is an aetiological factor in the pathogenesis of neurological degeneration diseases. These findings appear in Nature Medicine, online on 10 April 2005.

Epidemiological studies point to development of cancer in patients affected
Epidemiological and clinical studies have proposed that deficiency in the NBS1 function represents an important risk factor in the development of malignancies in NBS patients as well as in heterozygous carriers.

Public health consequences of some genotoxic treatment significant
Because the average carrier frequency of the NBS1 founder mutation is 1 in 177 among newborns in Slav populations in Central and Eastern Europe, even a moderately elevated cancer risk in heterozygous carriers could potentially result in several hundreds of new cancer cases in these populations. Therefore, it is important to note that any genotoxic treatment of the patients suffering from chromosome instability syndromes may well increase the risk of developing neuronal degeneration symptoms. Much more research is needed on these potential effects.


Pierre-Olivier Frappart, Wei-Min Tong, Ilja Demuth, Ivan Radovanovic, Zdenko Herceg, Adriano Aguzzi, Martin Digweed and Zhao-Qi Wang. An essential function for NBS1 in the prevention of ataxia and cerebellar defects. Nature Medicine DOI: 10.1038/nm1228 (2005).

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