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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Identification and functional consequences of a novel MRE11 mutation affecting 10 Saudi Arabian patients with the ataxia telangiectasia-like disorder
Human Molecular Genetics, Volume 14, No. 2, Year 2005
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Description
Ten new patients with ataxia telangiectasia-like disorder (ATLD) from three unrelated Saudi Arabian families have been identified aged 5-37 representing the largest cohort of ATLD patients ever identified. They presented with an early-onset, slowly progressive, ataxia plus ocular apraxia phenotype with an absence of tumor development, even in the oldest patient. Extra-neurological features such as telangiectasia, raised alpha-fetoprotein and reduced immunoglobulin levels were absent. No translocations were found in the two investigated patients, and the presence of microcephaly was noted in four out of eight ascertained patients. All patients are homozygous for a novel missense mutation (630G→C, W210C) of the MRE11 gene. The cellular consequences of this amino acid change, localized in the nuclease domain of the Mre11 protein, have been determined in fibroblast cultures established from two individuals. They showed high constitutive levels of Mre11 and Rad50 proteins compared with cells from normal individuals but a very low level of the Nbs1 protein. After exposure to ionizing radiation, a dose-dependent defect in ataxia telangiectasia mutated (ATM)-serine 1981, p53-serine 15 and Chk2 phosphorylation, and p53 stabilization were noted, together with a failure to form Mre11 foci and enhanced radiation sensitivity. Formation of γH2AX foci was similar to that seen in normal fibroblasts under the experimental conditions examined. These results emphasize the importance of functional interactions among the three proteins of the Mre11-Rad50-Nbs1 complex and lend support to a role of this complex as a sensor of DNA double-strand breaks, acting upstream of ATM. © Oxford University Press 2005; all rights reserved.
Authors & Co-Authors
Fernet, Marie
France, Lyon
Centre International de Recherche Sur le Cancer
France, Grenoble
Institut de Biologie Structurale
Gribaa, Moez
France, Illkirch-graffenstaden
Igbmc Institut de Genetique et de Biologie Moleculaire et Cellulaire
Tunisia, Sousse
Hopital Farhat Hached Sousse
Salih, Mustafa Abdalla M.
Saudi Arabia, Riyadh
College of Medicine
Seidahmed, Mohammed Zain
Saudi Arabia, Riyadh
Security Forces Hospital Program Riyadh
Hall, Janet
France, Lyon
Centre International de Recherche Sur le Cancer
Kœnig, Michel
France, Illkirch-graffenstaden
Igbmc Institut de Genetique et de Biologie Moleculaire et Cellulaire
Statistics
Citations: 133
Authors: 6
Affiliations: 6
Identifiers
Doi:
10.1093/hmg/ddi027
ISSN:
09646906
Research Areas
Cancer
Genetics And Genomics
Health System And Policy
Study Design
Cohort Study