Nijmegen breakage syndrome

Nijmegen breakage syndrome
Classification and external resources
OMIM 251260
DiseasesDB 32395
eMedicine derm/725
MeSH D049932

Nijmegen breakage syndrome (NBS), also known as Berlin breakage syndrome, ataxia telangiectasia variant 1 (AT-V1) and Seemanova syndrome,[1] is a rare autosomal recessive[2] congenital disorder causing chromosomal instability, probably as a result of a defect in the Double Holliday junction DNA repair mechanism and/or the Synthesis Dependent Strand Annealing mechanism for repairing double strand breaks in DNA (see Homologous recombination).[3]

NBS1 codes for a protein that has two major functions: (1) to stop the cell cycle in the S phase, when there are errors in the cell DNA (2) to interact with FANCD2 that can activate the BRCA1/BRCA2 pathway of DNA repair. This explains why mutations in the NBS1 gene lead to higher levels of cancer (see Fanconi anemia, Cockayne syndrome.)

The name derives from the Dutch city Nijmegen where the condition was first described.[4]

Most people with NBS have West Slavic origins. The largest number of them live in Poland.

Characteristics

It is characterized by microcephaly, a distinct facial appearance, short stature, immunodeficiency, radiation sensitivity and a strong predisposition to lymphoid malignancy.[5][6] NBS is caused by a mutation in the NBS1 gene. It is thus not surprising that many of the features are similar to ataxia telangiectasia (AT), and this syndrome is sometimes termed AT-variant 1; in AT, an abnormal ATM protein, the normal correlate of which interacts with the MRE11/RAD50/NBS1 (MRN) complex.[3]

Cause

Nijmegen breakage syndrome has an autosomal recessive pattern of inheritance.

NBS is caused by a mutation in the NBS1 gene, located at human chromosome 8q21.[7][8] The disease is inherited in an autosomal recessive manner.[2] This means the defective gene responsible for the disorder is located on an autosome (chromosome 8 is an autosome), and two copies of the defective gene (one inherited from each parent) are required in order to be born with the disorder. The parents of an individual with an autosomal recessive disorder both carry one copy of the defective gene, but usually do not experience any signs or symptoms of the disorder.

Two adult siblings, both heterozygous for two particular NBS1 nonsense mutations displayed cellular sensitivity to radiation, chromosome instability and fertility defects, but not the developmental defects that are typically found in other NBS patients.[9] These individuals appear to be primarily defective in homologous recombination, a process that accurately repairs double-strand breaks, both in somatic cells and during meiosis.

References

  1. ↑ Seemanova, E., Passarge, E., Beneskova, D., Houstek, J., Kasal, P., Sevcikova, M. Familial microcephaly with normal intelligence, immunodeficiency, and risk of lymphoreticular malignancies: a new autosomal recessive disorder. Am. J. Med. Genet. 20: 639-648, 1985. PMID 3857858
  2. 1 2 Cheung, V. G.; Ewens, W. J. (August 2006). "Heterozygous carriers of Nijmegen Breakage Syndrome have a distinct gene expression phenotype". Genome Research (Free full text) 16 (8): 973–979. doi:10.1101/gr.5320706. PMC 1524869. PMID 16809669.
  3. 1 2 http://omim.org/entry/251260
  4. ↑ Weemaes CM, Hustinx TW, Scheres JM, van Munster PJ, Bakkeren JA, Taalman RD. (1981). "A new chromosomal instability disorder: the Nijmegen breakage syndrome". Acta Paediatr Scand 70 (4): 557–64. doi:10.1111/j.1651-2227.1981.tb05740.x. PMID 7315300.
  5. ↑ Digweed M, Sperling K (2004). "Nijmegen breakage syndrome: clinical manifestation of defective response to DNA double-strand breaks". DNA Repair (Amst) 3 (8-9): 1207–17. doi:10.1016/j.dnarep.2004.03.004. PMID 15279809.
  6. ↑ "Nijmegen breakage syndrome. The International Nijmegen Breakage Syndrome Study Group". Arch Dis Child 82 (5): 400–6. 2000. doi:10.1136/adc.82.5.400. PMC 1718318. PMID 10799436. Full text
  7. ↑ Iijima K, Komatsu K, Matsuura S, Tauchi H (2004). "The Nijmegen breakage syndrome gene and its role in genome stability". Chromosoma 113 (2): 53–61. doi:10.1007/s00412-004-0298-0. PMID 15258809.
  8. ↑ Online 'Mendelian Inheritance in Man' (OMIM) 602667
  9. ↑ Warcoin M, Lespinasse J, Despouy G, Dubois d'Enghien C, Laugé A, Portnoï MF, Christin-Maitre S, Stoppa-Lyonnet D, Stern MH (2009). "Fertility defects revealing germline biallelic nonsense NBN mutations". Hum. Mutat. 30 (3): 424–30. doi:10.1002/humu.20904. PMID 19105185.

External links

This article is issued from Wikipedia - version of the Monday, October 26, 2015. The text is available under the Creative Commons Attribution/Share Alike but additional terms may apply for the media files.