Top

Published in:

01-11-2011 | ORIGINAL ARTICLE

New mutations in the ATM gene and clinical data of 25 AT patients

Authors: Ilja Demuth, Véronique Dutrannoy, Wilson Marques Jr, Heidemarie Neitzel, Detlev Schindler, Petja S. Dimova, Krystyna H. Chrzanowska, Veneta Bojinova, Hanna Gregorek, Luitgard M. Graul-Neumann, Arpad von Moers, Ilka Schulze, Marion Nicke, Elcin Bora, Tufan Cankaya, Éva Oláh, Csongor Kiss, Beáta Bessenyei, Katalin Szakszon, Ursula Gruber-Sedlmayr, Peter Michael Kroisel, Sigrun Sodia, Timm O. Goecke, Thilo Dörk, Martin Digweed, Karl Sperling, Joaquim de Sá, Charles Marques Lourenco, Raymonda Varon

Published in: Neurogenetics | Issue 4/2011

Abstract

Ataxia telangiectasia (AT) is an autosomal recessive disorder characterized by cerebellar degeneration, immunodeficiency, oculocutaneous telangiectasias, chromosomal instability, radiosensitivity, and cancer predisposition. The gene mutated in the patients, ATM, encodes a member of the phosphatidylinositol 3-kinase family proteins. The ATM protein has a key role in the cellular response to DNA damage. Truncating and splice site mutations in ATM have been found in most patients with the classical AT phenotype. Here we report of our extensive ATM mutation screening on 25 AT patients from 19 families of different ethnic origin. Previously unknown mutations were identified in six patients including a new homozygous missense mutation, c.8110T>C (p.Cys2704Arg), in a severely affected patient. Comprehensive clinical data are presented for all patients described here along with data on ATM function generated by analysis of cell lines established from a subset of the patients.

Boder E, Sedgwick RP (1958) Ataxia-telangiectasia; a familial syndrome of progressive cerebellar ataxia, oculocutaneous telangiectasia and frequent pulmonary infection. Pediatrics 21(4):526–554PubMed

Lavin MF, Shiloh Y (1997) The genetic defect in ataxia-telangiectasia. Annu Rev Immunol 15:177–202PubMedCrossRef

Taylor AM, Harnden DG, Arlett CF, Harcourt SA, Lehmann AR, Stevens S, Bridges BA (1975) Ataxia telangiectasia: a human mutation with abnormal radiation sensitivity. Nature 258(5534):427–429PubMedCrossRef

Savitsky K, Bar-Shira A, Gilad S, Rotman G, Ziv Y, Vanagaite L, Tagle DA, Smith S, Uziel T, Sfez S, Ashkenazi M, Pecker I, Frydman M, Harnik R, Patanjali SR, Simmons A, Clines GA, Sartiel A, Gatti RA, Chessa L, Sanal O, Lavin MF, Jaspers NG, Taylor AM, Arlett CF, Miki T, Weissman SM, Lovett M, Collins FS, Shiloh Y (1995) A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science 268(5218):1749–1753PubMedCrossRef

Bakkenist CJ, Kastan MB (2003) DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature 421(6922):499–506PubMedCrossRef

Daniel JA, Pellegrini M, Lee JH, Paull TT, Feigenbaum L, Nussenzweig A (2008) Multiple autophosphorylation sites are dispensable for murine ATM activation in vivo. J Cell Biol 183(5):777–783PubMedCrossRef

Matsuoka S, Ballif BA, Smogorzewska A, McDonald ER 3rd, Hurov KE, Luo J, Bakalarski CE, Zhao Z, Solimini N, Lerenthal Y, Shiloh Y, Gygi SP, Elledge SJ (2007) ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage. Science 316(5828):1160–1166PubMedCrossRef

Lavin MF (2008) Ataxia-telangiectasia: from a rare disorder to a paradigm for cell signalling and cancer. Nat Rev Mol Cell Biol 9(10):759–769PubMedCrossRef

Shiloh Y (2006) The ATM-mediated DNA-damage response: taking shape. Trends Biochem Sci 31(7):402–410PubMedCrossRef

10.

Platzer M, Rotman G, Bauer D, Uziel T, Savitsky K, Bar-Shira A, Gilad S, Shiloh Y, Rosenthal A (1997) Ataxia-telangiectasia locus: sequence analysis of 184 kb of human genomic DNA containing the entire ATM gene. Genome Res 7(6):592–605PubMed

11.

Fokkema IF, den Dunnen JT, Taschner PE (2005) LOVD: easy creation of a locus-specific sequence variation database using an “LSDB-in-a-box” approach. Hum Mutat 26(2):63–68PubMedCrossRef

12.

Lakin ND, Weber P, Stankovic T, Rottinghaus ST, Taylor AM, Jackson SP (1996) Analysis of the ATM protein in wild-type and ataxia telangiectasia cells. Oncogene 13(12):2707–2716PubMed

13.

Stankovic T, Kidd AM, Sutcliffe A, McGuire GM, Robinson P, Weber P, Bedenham T, Bradwell AR, Easton DF, Lennox GG, Haites N, Byrd PJ, Taylor AM (1998) ATM mutations and phenotypes in ataxia-telangiectasia families in the British Isles: expression of mutant ATM and the risk of leukemia, lymphoma, and breast cancer. Am J Hum Genet 62(2):334–345PubMedCrossRef

14.

Neitzel H (1986) A routine method for the establishment of permanent growing lymphoblastoid cell lines. Hum Genet 73(4):320–326PubMedCrossRef

15.

Demuth I, Digweed M, Concannon P (2004) Human SNM1B is required for normal cellular response to both DNA interstrand crosslink-inducing agents and ionizing radiation. Oncogene 23(53):8611–8618PubMedCrossRef

16.

Kubbies M, Hoehn H, Schindler D, Chen Y, Rabinovitch PS (1989) Cell cycle analysis via BrdU-Hoechst flow cytometry—principles and applications. In: Yen A (ed) Flow cytometry: advanced research and clinical applications, vol 2. CRC Press, Boca Raton, pp 6–28

17.

Rabinovitch PS, Kubbies M, Chen YC, Schindler D, Hoehn H (1988) BrdU-Hoechst flow cytometry: a unique tool for quantitative cell cycle analysis. Exp Cell Res 174(2):309–318PubMedCrossRef

18.

Schindler D, Hoehn H (1999) Flow cytometric testing for syndromes with chromosomal instability, aplastic anemia and related hematological disorders. In: Wegner RD (ed) Diagnostic cytogenetics—Springer lab manual. Springer, Heidelberg, pp 269–281

19.

Seyschab H, Sun Y, Friedl R, Schindler D, Hoehn H (1993) G2 phase cell cycle disturbance as a manifestation of genetic cell damage. Hum Genet 92(1):61–68PubMedCrossRef

20.

Sandoval N, Platzer M, Rosenthal A, Dork T, Bendix R, Skawran B, Stuhrmann M, Wegner RD, Sperling K, Banin S, Shiloh Y, Baumer A, Bernthaler U, Sennefelder H, Brohm M, Weber BH, Schindler D (1999) Characterization of ATM gene mutations in 66 ataxia telangiectasia families. Hum Mol Genet 8(1):69–79PubMedCrossRef

21.

Baumer A, Bernthaler U, Wolz W, Hoehn H, Schindler D (1996) New mutations in the ataxia telangiectasia gene. Hum Genet 98(2):246–249PubMedCrossRef

22.

Gilad S, Bar-Shira A, Harnik R, Shkedy D, Ziv Y, Khosravi R, Brown K, Vanagaite L, Xu G, Frydman M, Lavin MF, Hill D, Tagle DA, Shiloh Y (1996) Ataxia-telangiectasia: founder effect among North African Jews. Hum Mol Genet 5(12):2033–2037PubMedCrossRef

23.

Teraoka SN, Telatar M, Becker-Catania S, Liang T, Onengut S, Tolun A, Chessa L, Sanal O, Bernatowska E, Gatti RA, Concannon P (1999) Splicing defects in the ataxia-telangiectasia gene, ATM: underlying mutations and consequences. Am J Hum Genet 64(6):1617–1631PubMedCrossRef

24.

Gilad S, Chessa L, Khosravi R, Russell P, Galanty Y, Piane M, Gatti RA, Jorgensen TJ, Shiloh Y, Bar-Shira A (1998) Genotype–phenotype relationships in ataxia-telangiectasia and variants. Am J Hum Genet 62(3):551–561PubMedCrossRef

25.

Hiel JA, van Engelen BG, Weemaes CM, Broeks A, Verrips A, ter Laak H, Vingerhoets HM, van den Heuvel LP, Lammens M, Gabreels FJ, Last JI, Taylor AM (2006) Distal spinal muscular atrophy as a major feature in adult-onset ataxia telangiectasia. Neurology 67(2):346–349PubMedCrossRef

26.

Verhagen MM, Abdo WF, Willemsen MA, Hogervorst FB, Smeets DF, Hiel JA, Brunt ER, van Rijn MA, Majoor Krakauer D, Oldenburg RA, Broeks A, Last JI, van't Veer LJ, Tijssen MA, Dubois AM, Kremer HP, Weemaes CM, Taylor AM, van Deuren M (2009) Clinical spectrum of ataxia-telangiectasia in adulthood. Neurology 73(6):430–437PubMedCrossRef

27.

Scott SP, Bendix R, Chen P, Clark R, Dork T, Lavin MF (2002) Missense mutations but not allelic variants alter the function of ATM by dominant interference in patients with breast cancer. Proc Natl Acad Sci U S A 99(2):925–930PubMedCrossRef

28.

Mitui M, Campbell C, Coutinho G, Sun X, Lai CH, Thorstenson Y, Castellvi-Bel S, Fernandez L, Monros E, Carvalho BT, Porras O, Fontan G, Gatti RA (2003) Independent mutational events are rare in the ATM gene: haplotype prescreening enhances mutation detection rate. Hum Mutat 22(1):43–50PubMedCrossRef

29.

Sasaki T, Tian H, Kukita Y, Inazuka M, Tahira T, Imai T, Yamauchi M, Saito T, Hori T, Hashimoto-Tamaoki T, Komatsu K, Nikaido O, Hayashi K (1998) ATM mutations in patients with ataxia telangiectasia screened by a hierarchical strategy. Hum Mutat 12(3):186–195PubMedCrossRef

30.

Byrd PJ, Cooper PR, Stankovic T, Kullar HS, Watts GD, Robinson PJ, Taylor MR (1996) A gene transcribed from the bidirectional ATM promoter coding for a serine rich protein: amino acid sequence, structure and expression studies. Hum Mol Genet 5(11):1785–1791PubMedCrossRef

31.

Coutinho G, Mitui M, Campbell C, Costa Carvalho BT, Nahas S, Sun X, Huo Y, Lai CH, Thorstenson Y, Tanouye R, Raskin S, Kim CA, Llerena J Jr, Gatti RA (2004) Five haplotypes account for fifty-five percent of ATM mutations in Brazilian patients with ataxia telangiectasia: seven new mutations. Am J Med Genet A 126A(1):33–40PubMedCrossRef

32.

Wright J, Teraoka S, Onengut S, Tolun A, Gatti RA, Ochs HD, Concannon P (1996) A high frequency of distinct ATM gene mutations in ataxia-telangiectasia. Am J Hum Genet 59(4):839–846PubMed

33.

Gilad S, Khosravi R, Shkedy D, Uziel T, Ziv Y, Savitsky K, Rotman G, Smith S, Chessa L, Jorgensen TJ, Harnik R, Frydman M, Sanal O, Portnoi S, Goldwicz Z, Jaspers NG, Gatti RA, Lenoir G, Lavin MF, Tatsumi K, Wegner RD, Shiloh Y, Bar-Shira A (1996) Predominance of null mutations in ataxia-telangiectasia. Hum Mol Genet 5(4):433–439PubMedCrossRef

34.

Birrell GW, Kneebone K, Nefedov M, Nefedova E, Jartsev MN, Mitsui M, Gatti RA, Lavin MF (2005) ATM mutations, haplotype analysis, and immunological status of Russian patients with ataxia telangiectasia. Hum Mutat 25(6):593PubMedCrossRef

35.

Broeks A, de Klein A, Floore AN, Muijtjens M, Kleijer WJ, Jaspers NG, van't Veer LJ (1998) ATM germline mutations in classical ataxia-telangiectasia patients in the Dutch population. Hum Mutat 12(5):330–337PubMedCrossRef

36.

McConville CM, Stankovic T, Byrd PJ, McGuire GM, Yao QY, Lennox GG, Taylor MR (1996) Mutations associated with variant phenotypes in ataxia-telangiectasia. Am J Hum Genet 59(2):320–330PubMed

37.

Gilad S, Khosravi R, Harnik R, Ziv Y, Shkedy D, Galanty Y, Frydman M, Levi J, Sanal O, Chessa L, Smeets D, Shiloh Y, Bar-Shira A (1998) Identification of ATM mutations using extended RT-PCR and restriction endonuclease fingerprinting, and elucidation of the repertoire of A-T mutations in Israel. Hum Mutat 11(1):69–75PubMedCrossRef

38.

Mitui M, Nahas SA, Du LT, Yang Z, Lai CH, Nakamura K, Arroyo S, Scott S, Purayidom A, Concannon P, Lavin M, Gatti RA (2009) Functional and computational assessment of missense variants in the ataxia-telangiectasia mutated (ATM) gene: mutations with increased cancer risk. Hum Mutat 30(1):12–21PubMedCrossRef

39.

Larson GP, Zhang G, Ding S, Foldenauer K, Udar N, Gatti RA, Neuberg D, Lunetta KL, Ruckdeschel JC, Longmate J, Flanagan S, Krontiris TG (1997) An allelic variant at the ATM locus is implicated in breast cancer susceptibility. Genet Test 1(3):165–170PubMedCrossRef

40.

Sommer SS, Buzin CH, Jung M, Zheng J, Liu Q, Jeong SJ, Moulds J, Nguyen VQ, Feng J, Bennett WP, Dritschilo A (2002) Elevated frequency of ATM gene missense mutations in breast cancer relative to ethnically matched controls. Cancer Genet Cytogenet 134(1):25–32PubMedCrossRef

Title: New mutations in the ATM gene and clinical data of 25 AT patients
Authors: Ilja Demuth
Véronique Dutrannoy
Wilson Marques Jr
Heidemarie Neitzel
Detlev Schindler
Petja S. Dimova
Krystyna H. Chrzanowska
Veneta Bojinova
Hanna Gregorek
Luitgard M. Graul-Neumann
Arpad von Moers
Ilka Schulze
Marion Nicke
Elcin Bora
Tufan Cankaya
Éva Oláh
Csongor Kiss
Beáta Bessenyei
Katalin Szakszon
Ursula Gruber-Sedlmayr
Peter Michael Kroisel
Sigrun Sodia
Timm O. Goecke
Thilo Dörk
Martin Digweed
Karl Sperling
Joaquim de Sá
Charles Marques Lourenco
Raymonda Varon
Publication date: 01-11-2011
Publisher: Springer-Verlag
Published in: Neurogenetics / Issue 4/2011
Print ISSN: 1364-6745
Electronic ISSN: 1364-6753
DOI: https://doi.org/10.1007/s10048-011-0299-0

Keynote webinar | Spotlight on medication adherence

Springer Medicine

New mutations in the ATM gene and clinical data of 25 AT patients

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 4/2011

Late-onset Alzheimer's disease is associated with mitochondrial DNA 7028C/haplogroup H and D310 poly-C tract heteroplasmy

A novel deletion–insertion mutation identified in exon 3 of FXN in two siblings with a severe Friedreich ataxia phenotype

A nullimorphic ERLIN2 mutation defines a complicated hereditary spastic paraplegia locus (SPG18)

Acknowledgement to Referees 2010/2011

Genetic variability in SNCA and Parkinson’s disease

Shorter telomeres in patients with cerebral autosomal dominant arteriopathy and leukoencephalopathy (CADASIL)