Human RAD50 deficiency in a Nijmegen breakage syndrome-like disorder.

Waltes, R, Kalb, R, Gatei, M, Kijas, AW, Stumm, M, Sobeck, A, Wieland, B, Varon, R, Lerenthal Y, Lavin, Martin F., Schindler, D and Dörk, T (2009) Human RAD50 deficiency in a Nijmegen breakage syndrome-like disorder.. American Journal of Human Genetics, 84 5: 605-616. doi:10.1016/j.ajhg.2009.04.010

Author Waltes, R
Kalb, R
Gatei, M
Kijas, AW
Stumm, M
Sobeck, A
Wieland, B
Varon, R
Lerenthal Y
Lavin, Martin F.
Schindler, D
Dörk, T
Title Human RAD50 deficiency in a Nijmegen breakage syndrome-like disorder.
Journal name American Journal of Human Genetics   Check publisher's open access policy
ISSN 0002-9297
Publication date 2009-05-01
Year available 2009
Sub-type Article (original research)
DOI 10.1016/j.ajhg.2009.04.010
Volume 84
Issue 5
Start page 605
End page 616
Total pages 12
Place of publication United States
Publisher Cell Press
Language eng
Subject C1
Abstract The MRE11/RAD50/NBN (MRN) complex plays a key role in recognizing and signaling DNA double-strand breaks (DSBs). Hypomorphic mutations in NBN (previously known as NBS1) and MRE11A give rise to the autosomal-recessive diseases Nijmegen breakage syndrome (NBS) and ataxia-telangiectasia-like disorder (ATLD), respectively. To date, no disease due to RAD50 deficiency has been described. Here, we report on a patient previously diagnosed as probably having NBS, with microcephaly, mental retardation, 'bird-like' face, and short stature. At variance with this diagnosis, she never had severe infections, had normal immunoglobulin levels, and did not develop lymphoid malignancy up to age 23 years. We found that she is compound heterozygous for mutations in the RAD50 gene that give rise to low levels of unstable RAD50 protein. Cells from the patient were characterized by chromosomal instability; radiosensitivity; failure to form DNA damage-induced MRN foci; and impaired radiation-induced activation of and downstream signaling through the ATM protein, which is defective in the human genetic disorder ataxia-telangiectasia. These cells were also impaired in G1/S cell-cycle-checkpoint activation and displayed radioresistant DNA synthesis and G2-phase accumulation. The defective cellular phenotype was rescued by wild-type RAD50. In conclusion, we have identified and characterized a patient with a RAD50 deficiency that results in a clinical phenotype that can be classified as an NBS-like disorder (NBSLD).
Keyword Nijmegen Breakage Syndrome
Q-Index Code C1
Q-Index Status Confirmed Code

Document type: Journal Article
Sub-type: Article (original research)
Collections: UQ Centre for Clinical Research Publications
2010 Higher Education Research Data Collection
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Created: Thu, 08 Oct 2009, 00:06:45 EST by Carmen Buttery on behalf of UQ Centre for Clinical Research