Skip Navigation



Human Molecular Genetics Advance Access published online on July 21, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddh221
© 2004 by Oxford University Press
This Article
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
13/18/2155    most recent
ddh221v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Delia, D.
Right arrow Articles by Chessa, L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Delia, D.
Right arrow Articles by Chessa, L.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Article

MRE11 mutations and impaired ATM-dependent responses in an Italian family with Ataxia-Telangiectasia Like Disorder (ATLD)

Domenico Delia 1, Maria Piane 2, Giacomo Buscemi 1, Camilla Savio 2, Silvia Palmeri 3, Patrizia Lulli 2, Luigi Carlessi 1, Enrico Fontanella 1, Luciana Chessa 4*

1 Department of Experimental Oncology, Istituto Nazionale Tumori, Via G. Venezian 1, 20133 Milano, Italy
2 Department of Experimental Medicine Pathology, II Faculty of Medicine, University "La Sapienza", Roma, Italy
3 Department of Neurological Sciences, Policlinico Le Scotte, University of Siena, 53100 Siena, Italy
4 Department of Experimental Medicine Pathology, II Faculty of Medicine, University "La Sapienza", A.O. S. Andrea, Via di Grottarossa 1035, I-00189 Roma, Italy

* To whom correspondence should be addressed. E-mail: luciana.chessa{at}uniroma1.it.


  Abstract

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; 1714C->T, R571X]. The 1422C->A allele was inherited from the mother, whereas the 1714C->T, paternally inherited, was apparently null as result of non-sense mediated mRNA decay (NMD). Interestingly, the 1714C->T mutation is the same previously identified in an unrelated English ATLD family (probands ATLD3 and ATLD4), suggesting an important role for NMD in saving potentially lethal mutations. Lymphoblastoid cells (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 {gamma}-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, that rationalizes the clinical similarity between A-T and ATLD.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Hum Mol GenetHome page
J. L. Harris, B. Jakob, G. Taucher-Scholz, G. L. Dianov, O. J. Becherel, and M. F. Lavin
Aprataxin, poly-ADP ribose polymerase 1 (PARP-1) and apurinic endonuclease 1 (APE1) function together to protect the genome against oxidative damage
Hum. Mol. Genet., November 1, 2009; 18(21): 4102 - 4117.
[Abstract] [Full Text] [PDF]

Home page
 Phil Trans R Soc BHome page
A. Kotnis, L. Du, C. Liu, S. W Popov, and Q. Pan-Hammarstrom
Non-homologous end joining in class switch recombination: the beginning of the end
Phil Trans R Soc B, March 12, 2009; 364(1517): 653 - 665.
[Abstract] [Full Text] [PDF]

Home page
 CarcinogenesisHome page
K. Heikkinen, K. Rapakko, S.-M. Karppinen, H. Erkko, S. Knuutila, T. Lundan, A. Mannermaa, A.-L. Borresen-Dale, A. Borg, R. B. Barkardottir, et al.
RAD50 and NBS1 are breast cancer susceptibility genes associated with genomic instability
Carcinogenesis, August 1, 2006; 27(8): 1593 - 1599.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Pathol.Home page
A M R Taylor and P J Byrd
Molecular pathology of ataxia telangiectasia
J. Clin. Pathol., October 1, 2005; 58(10): 1009 - 1015.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
Z. You, C. Chahwan, J. Bailis, T. Hunter, and P. Russell
ATM Activation and Its Recruitment to Damaged DNA Require Binding to the C Terminus of Nbs1
Mol. Cell. Biol., July 1, 2005; 25(13): 5363 - 5379.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
Y. Yang and K. Herrup
Loss of Neuronal Cell Cycle Control in Ataxia-Telangiectasia: A Unified Disease Mechanism
J. Neurosci., March 9, 2005; 25(10): 2522 - 2529.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
M. Fernet, M. Gribaa, M. A.M. Salih, M. Z. Seidahmed, J. Hall, and M. Koenig
Identification and functional consequences of a novel MRE11 mutation affecting 10 Saudi Arabian patients with the ataxia telangiectasia-like disorder
Hum. Mol. Genet., January 15, 2005; 14(2): 307 - 318.
[Abstract] [Full Text] [PDF]


Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.