Human Molecular Genetics Advance Access originally published online on December 1, 2004
Human Molecular Genetics 2005 14(2):307-318; doi:10.1093/hmg/ddi027
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Human Molecular Genetics, Vol. 14, No. 2 © Oxford University Press 2005; all rights reserved
Identification and functional consequences of a novel MRE11 mutation affecting 10 Saudi Arabian patients with the ataxia telangiectasia-like disorder
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1DNA Repair Team, International Agency for Research on Cancer, 150 cours Albert Thomas, Lyon 69372, France, 2Institut de Génétique et de Biologie Moléculaire et Cellulaire (CNRS/INSERM/ULP), Illkirch - Strasbourg 67404, France, 3Service de Génétique et de Cytogénétique, Hôpital Universitaire Farhat Hached, Sousse, Tunisia, 4Division of Paediatric Neurology, Department of Paediatrics, College of Medicine, King Saud University, Riyadh 11461, Saudi Arabia and 5Department of Paediatrics, Security Forces Hospital, Riyadh 11481, Saudi Arabia
* To whom correspondence should be addressed. Tel: +33 472738596; Fax: +33 472738322; Email: hall{at}iarc.fr
Received September 14, 2004; Accepted November 16, 2004
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 
H2AX 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.
The authors with it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
Present address: Laboratoire ‘Protéines du Cytosquelette’, Institut de Biologie Structurale, 41, rue Jules Horowitz, 38027 Grenoble Cedex 1, France.
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