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Nijmegen breakage syndrome

Author
Andrew Gennery, MD
Section Editor
E Richard Stiehm, MD
Deputy Editor
Elizabeth TePas, MD, MS

INTRODUCTION

A number of human genetic disorders cause chromosomal breakage, which is characterized by genome instability that occurs in the basal state (spontaneously) or in response to DNA-damaging agents (table 1). These disorders cause defects in the recognition and/or repair of damage to DNA inflicted by different agents. In most cases, the genome instability is associated with immunodeficiency, a predisposition to develop cancer, and premature aging [1].

This topic review will discuss Nijmegen breakage syndrome (NBS; MIM #251260), which is a chromosomal breakage syndrome associated with immunodeficiency [2,3]. Discussions relating to similar disorders are presented separately. (See "Ataxia-telangiectasia" and "Bloom syndrome".)

EPIDEMIOLOGY

Nijmegen breakage syndrome (NBS) is a rare disorder. The exact incidence is unknown. Most NBS patients have an ethnic origin from Eastern Europe, notably Poland and Czechoslovakia [4,5]. One study analyzed newborn screening cards for the most common NBS mutation (657del5) [5]. The prevalence of this mutation ranged from 1 in 154 to 1 in 190 in three Slavic populations, compared with 1 in 866 in a German population reported in a separate study [6]. The incidence of NBS was estimated to be 1 in 95,000 livebirths in Czechoslovakia [5].

PATHOGENESIS

Nijmegen breakage syndrome (NBS) is an autosomal recessive chromosomal instability disorder that is caused by mutations in the nibrin (NBN) gene on 8q21 that encodes the protein nibrin (MIM #602667) [7]. The most common mutation in patients of Eastern European descent is hypomorphic, leading to a partially functional protein [8]. Other mutations are more common in different populations [3].

Nibrin forms a complex with MRE11 (meiotic recombination 11, the protein mutated in ataxia-telangiectasia-like disorder) and RAD50 (a protein involved in deoxyribonucleic acid [DNA] double-strand break repair) and then rapidly localizes to the site of DNA double-strand breaks. DNA breaks are not efficiently repaired in the absence of nibrin [9-11]. This protein complex is also involved in meiotic recombination and telomere maintenance [12-14]. In addition, nibrin plays a role in the initiation of base excision repair after oxidative or alkylating stress [15].

       

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Literature review current through: Nov 2016. | This topic last updated: Wed Jul 15 00:00:00 GMT+00:00 2015.
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