Introduction

Nijmegen breakage syndrome (NBS, MIM 251260) is extremely rare. Inheritance follows an autosomal recessive modus with complete penetrance. We are aware of some 70 families worldwide, the majority of which are in central and eastern Europe. The observed carrier frequency in Poland, Ukraine, and the Czech Republic is 1:177; however, considerably fewer than the expected 1:95,000 patients have been currently ascertained (1).

Historically, NBS belongs to the chromosomal instability syndromes. Based on the clinical and cellular similarity to ataxia-telangiectasia (AT) (2,3), NBS has long been regarded as an AT variant. However, early complementation experiments using cell fusion among AT and NBS cells suggested (that) different genetic defects underlie AT and NBS. The genetic localization and subsequent cloning of the gene defective in patients with NBS ultimately separated the two genetic entities AT and NBS. Recent molecular data, however, demonstrate that the ATM and NBS1 gene products may be closely, even directly, linked in the cellular response to DNA damage following ionizing radiation. Thus, this chapter will include some limited information on AT (see Chapter 13) for comparative reasons. In addition to reviewing the phenotypic NBS characteristics as well as the cloning of NBS1, recent advances in the characterization of the NBS1 gene product and its presumed role in various cellular pathways will be summarized.

Some chromosomal instability syndromes are clinically characterized by premature aging. According to the "disposable soma theory" (4,5), aging can be regarded as the process of accumulating somatic damage. Cellular and organismic aging also has been shown to correlate with the telomere metabolism (6) (see Chapter 13). Therefore, this chapter will include information on the known and putative roles of the NBS1 gene product in repairing cellular damage (i.e., DNA damage and the telomere metabolism), as well as the possible implications for aging processes at the cellular and organismal levels.

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