Nijmegen breakage syndrome
- Andrew Gennery, MD
Andrew Gennery, MD
- Clinical Reader/Consultant
- Newcastle University
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 .
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".)
NBS is a rare disorder. The exact incidence is unknown. Most reported NBS patients have an ethnic origin from Eastern Europe, notably Poland, the Czech Republic, and Ukraine [4,5]. One study analyzed newborn screening cards for the most common NBS mutation (657del5) . 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 . The incidence of NBS was estimated to be 1 in 95,000 livebirths in Czechoslovakia .
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) . The most common mutation in patients of Eastern European descent is hypomorphic, leading to a partially functional protein . Other mutations are more common in different populations .
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 .To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
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