RGD Reference Report - Identification and functional consequences of a novel MRE11 mutation affecting 10 Saudi Arabian patients with the ataxia telangiectasia-like disorder.

General

Identification and functional consequences of a novel MRE11 mutation affecting 10 Saudi Arabian patients with the ataxia telangiectasia-like disorder.
Authors:	Fernet, M Gribaa, M Salih, MA Seidahmed, MZ Hall, J Koenig, M
Citation:	Fernet M, etal., Hum Mol Genet. 2005 Jan 15;14(2):307-18. Epub 2004 Dec 1.
RGD ID:	2317722
Pubmed:	PMID:15574463 (View Abstract at PubMed)
DOI:	DOI:10.1093/hmg/ddi027 (Journal Full-text)
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 gammaH2AX 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.

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Object Symbol	Species	Term	Qualifier	Evidence	With	Notes	Source	Original Reference(s)
MRE11	Human	Neurocutaneous Syndromes		IAGP		DNA:missense mutation:cds:W210C (human)	RGD
Mre11	Rat	Neurocutaneous Syndromes		ISO	MRE11 (Homo sapiens)	DNA:missense mutation:cds:W210C (human)	RGD
Mre11a	Mouse	Neurocutaneous Syndromes		ISO	MRE11 (Homo sapiens)	DNA:missense mutation:cds:W210C (human)	RGD

Objects Annotated

Genes (Rattus norvegicus)

Mre11 (MRE11 homolog, double strand break repair nuclease)

Genes (Mus musculus)

Mre11a (MRE11A homolog A, double strand break repair nuclease)

Genes (Homo sapiens)

MRE11 (MRE11 homolog, double strand break repair nuclease)

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Identification and functional consequences of a novel MRE11 mutation affecting 10 Saudi Arabian patients with the ataxia telangiectasia-like disorder.