Human Molecular Genetics Advance Access originally published online on July 21, 2004
Human Molecular Genetics 2004 13(18):2155-2163; doi:10.1093/hmg/ddh221
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Human Molecular Genetics, Vol. 13, No. 18 © Oxford University Press 2004; all rights reserved
MRE11 mutations and impaired ATM-dependent responses in an Italian family with ataxia-telangiectasia-like disorder
1Department of Experimental Oncology, Istituto Nazionale Tumori, Via G. Venezian 1, 20133 Milano, Italy, 2Department of Experimental Medicine and Pathology, II Faculty of Medicine, University ‘La Sapienza’, Roma, Italy and 3Department of Neurological Sciences, Policlinico Le Scotte, University of Siena, 53100 Siena, Italy
Received June 22, 2004; Accepted July 9, 2004
Hypomorphic mutations of the MRE11 gene are the hallmark of the radiosensitive ataxia-telangiectasia-like disorder (ATLD). Here, we describe a new family with two affected siblings, ATLD5 and ATLD6, now aged 37 and 36, respectively. They presented with late onset cerebellar degeneration slowly progressing until puberty and absence of telangiectasias, and were cancer-free. Both patients were wild-type for ATM and NBS1, but compound heterozygotes for MRE11 gene mutations [1422C
A, T481K; 1714CT, R571X]. The 1422CA allele was inherited from the mother, whereas the 1714CT, allele paternally inherited, was apparently null as a result of nonsense-mediated mRNA decay (NMD). Interestingly, the 1714CT mutation is the same as previously identified in an unrelated English ATLD family (probands ATLD3 and ATLD4), suggesting an important role for NMD in saving potentially lethal mutations. Lymphoblastoid cell lines (LCLs) derived from ATLD5 and ATLD6 were normal for ATM, but defective for Mre11, Rad50 and Nbs1 (the MRN complex) protein expression. Their response to 
-radiation was abnormal, as evidenced by the enhanced radiosensitivity, attenuated autophosphorylation of ATM-S1981 and phosphorylation of the ATM targets p53–S15 and Smc1–S966, failure to form Mre11 nuclear foci and defective G1 checkpoint arrest. The fibroblasts, but not LCLs, from ATLD5 and ATLD6 showed an impaired ATM-dependent Chk2 phosphorylation. These findings further underscore the interconnection between ATM activity and MRN function, which rationalizes the clinical similarity between ataxia-telangiectasia (A-T) and ATLD.
* To whom correspondence should be addressed at: II Faculty of Medicine, A.O.S. Andrea, Via di Grottarossa 1035, I-00189 Roma, Italy. Tel/Fax: +39 0680345258; Email: luciana.chessa{at}uniroma1.it
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