Skip to main content
NCBI home page
American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 1999 Jun;64(6):1617–1631. doi: 10.1086/302418

Splicing defects in the ataxia-telangiectasia gene, ATM: underlying mutations and consequences.

S N Teraoka 1, M Telatar 1, S Becker-Catania 1, T Liang 1, S Onengüt 1, A Tolun 1, L Chessa 1, O Sanal 1, E Bernatowska 1, R A Gatti 1, P Concannon 1
PMCID: PMC1377904  PMID: 10330348

Abstract

Mutations resulting in defective splicing constitute a significant proportion (30/62 [48%]) of a new series of mutations in the ATM gene in patients with ataxia-telangiectasia (AT) that were detected by the protein-truncation assay followed by sequence analysis of genomic DNA. Fewer than half of the splicing mutations involved the canonical AG splice-acceptor site or GT splice-donor site. A higher percentage of mutations occurred at less stringently conserved sites, including silent mutations of the last nucleotide of exons, mutations in nucleotides other than the conserved AG and GT in the consensus splice sites, and creation of splice-acceptor or splice-donor sites in either introns or exons. These splicing mutations led to a variety of consequences, including exon skipping and, to a lesser degree, intron retention, activation of cryptic splice sites, or creation of new splice sites. In addition, 5 of 12 nonsense mutations and 1 missense mutation were associated with deletion in the cDNA of the exons in which the mutations occurred. No ATM protein was detected by western blotting in any AT cell line in which splicing mutations were identified. Several cases of exon skipping in both normal controls and patients for whom no underlying defect could be found in genomic DNA were also observed, suggesting caution in the interpretation of exon deletions observed in ATM cDNA when there is no accompanying identification of genomic mutations.

Full Text

The Full Text of this article is available as a PDF (456.1 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aoufouchi S., Yélamos J., Milstein C. Nonsense mutations inhibit RNA splicing in a cell-free system: recognition of mutant codon is independent of protein synthesis. Cell. 1996 May 3;85(3):415–422. doi: 10.1016/s0092-8674(00)81119-8. [DOI] [PubMed] [Google Scholar]
  2. Athma P., Rappaport R., Swift M. Molecular genotyping shows that ataxia-telangiectasia heterozygotes are predisposed to breast cancer. Cancer Genet Cytogenet. 1996 Dec;92(2):130–134. doi: 10.1016/s0165-4608(96)00328-7. [DOI] [PubMed] [Google Scholar]
  3. Beaudet A. L., Tsui L. C. A suggested nomenclature for designating mutations. Hum Mutat. 1993;2(4):245–248. doi: 10.1002/humu.1380020402. [DOI] [PubMed] [Google Scholar]
  4. Belgrader P., Maquat L. E. Nonsense but not missense mutations can decrease the abundance of nuclear mRNA for the mouse major urinary protein, while both types of mutations can facilitate exon skipping. Mol Cell Biol. 1994 Sep;14(9):6326–6336. doi: 10.1128/mcb.14.9.6326. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Chen G., Lee EYHP The product of the ATM gene is a 370-kDa nuclear phosphoprotein. J Biol Chem. 1996 Dec 27;271(52):33693–33697. doi: 10.1074/jbc.271.52.33693. [DOI] [PubMed] [Google Scholar]
  6. Concannon P., Gatti R. A. Diversity of ATM gene mutations detected in patients with ataxia-telangiectasia. Hum Mutat. 1997;10(2):100–107. doi: 10.1002/(SICI)1098-1004(1997)10:2<100::AID-HUMU2>3.0.CO;2-O. [DOI] [PubMed] [Google Scholar]
  7. Cooper T. A., Mattox W. The regulation of splice-site selection, and its role in human disease. Am J Hum Genet. 1997 Aug;61(2):259–266. doi: 10.1086/514856. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Curry C. J., O'Lague P., Tsai J., Hutchison H. T., Jaspers N. G., Wara D., Gatti R. A., Hutchinson H. T. ATFresno: a phenotype linking ataxia-telangiectasia with the Nijmegen breakage syndrome. Am J Hum Genet. 1989 Aug;45(2):270–275. [PMC free article] [PubMed] [Google Scholar]
  9. Dietz H. C., Valle D., Francomano C. A., Kendzior R. J., Jr, Pyeritz R. E., Cutting G. R. The skipping of constitutive exons in vivo induced by nonsense mutations. Science. 1993 Jan 29;259(5095):680–683. doi: 10.1126/science.8430317. [DOI] [PubMed] [Google Scholar]
  10. Dörk T., Westermann S., Dittrich O., Twardowski M., Karstens J. H., Schmidtke J., Stuhrmann M. A frequent polymorphism of the gene mutated in ataxia telangiectasia. Mol Cell Probes. 1997 Feb;11(1):71–73. doi: 10.1006/mcpr.1996.0079. [DOI] [PubMed] [Google Scholar]
  11. Easton D. F. Cancer risks in A-T heterozygotes. Int J Radiat Biol. 1994 Dec;66(6 Suppl):S177–S182. doi: 10.1080/09553009414552011. [DOI] [PubMed] [Google Scholar]
  12. FitzGerald M. G., Bean J. M., Hegde S. R., Unsal H., MacDonald D. J., Harkin D. P., Finkelstein D. M., Isselbacher K. J., Haber D. A. Heterozygous ATM mutations do not contribute to early onset of breast cancer. Nat Genet. 1997 Mar;15(3):307–310. doi: 10.1038/ng0397-307. [DOI] [PubMed] [Google Scholar]
  13. Gatti R. A. Localizing the genes for ataxia-telangiectasia: a human model for inherited cancer susceptibility. Adv Cancer Res. 1991;56:77–104. doi: 10.1016/s0065-230x(08)60478-9. [DOI] [PubMed] [Google Scholar]
  14. Gilad S., Chessa L., Khosravi R., Russell P., Galanty Y., Piane M., Gatti R. A., Jorgensen T. J., Shiloh Y., Bar-Shira A. Genotype-phenotype relationships in ataxia-telangiectasia and variants. Am J Hum Genet. 1998 Mar;62(3):551–561. doi: 10.1086/301755. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Gilad S., Khosravi R., Shkedy D., Uziel T., Ziv Y., Savitsky K., Rotman G., Smith S., Chessa L., Jorgensen T. J. Predominance of null mutations in ataxia-telangiectasia. Hum Mol Genet. 1996 Apr;5(4):433–439. doi: 10.1093/hmg/5.4.433. [DOI] [PubMed] [Google Scholar]
  16. Hoffmeyer S., Nürnberg P., Ritter H., Fahsold R., Leistner W., Kaufmann D., Krone W. Nearby stop codons in exons of the neurofibromatosis type 1 gene are disparate splice effectors. Am J Hum Genet. 1998 Feb;62(2):269–277. doi: 10.1086/301715. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Hull J., Shackleton S., Harris A. The stop mutation R553X in the CFTR gene results in exon skipping. Genomics. 1994 Jan 15;19(2):362–364. doi: 10.1006/geno.1994.1070. [DOI] [PubMed] [Google Scholar]
  18. Huo Y. K., Wang Z., Hong J. H., Chessa L., McBride W. H., Perlman S. L., Gatti R. A. Radiosensitivity of ataxia-telangiectasia, X-linked agammaglobulinemia, and related syndromes using a modified colony survival assay. Cancer Res. 1994 May 15;54(10):2544–2547. [PubMed] [Google Scholar]
  19. Krawczak M., Reiss J., Cooper D. N. The mutational spectrum of single base-pair substitutions in mRNA splice junctions of human genes: causes and consequences. Hum Genet. 1992 Sep-Oct;90(1-2):41–54. doi: 10.1007/BF00210743. [DOI] [PubMed] [Google Scholar]
  20. Lakin N. D., Weber P., Stankovic T., Rottinghaus S. T., Taylor A. M., Jackson S. P. Analysis of the ATM protein in wild-type and ataxia telangiectasia cells. Oncogene. 1996 Dec 19;13(12):2707–2716. [PubMed] [Google Scholar]
  21. Liu W., Qian C., Francke U. Silent mutation induces exon skipping of fibrillin-1 gene in Marfan syndrome. Nat Genet. 1997 Aug;16(4):328–329. doi: 10.1038/ng0897-328. [DOI] [PubMed] [Google Scholar]
  22. Maquat L. E. When cells stop making sense: effects of nonsense codons on RNA metabolism in vertebrate cells. RNA. 1995 Jul;1(5):453–465. [PMC free article] [PubMed] [Google Scholar]
  23. Mazoyer S., Puget N., Perrin-Vidoz L., Lynch H. T., Serova-Sinilnikova O. M., Lenoir G. M. A BRCA1 nonsense mutation causes exon skipping. Am J Hum Genet. 1998 Mar;62(3):713–715. doi: 10.1086/301768. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. McConville C. M., Stankovic T., Byrd P. J., McGuire G. M., Yao Q. Y., Lennox G. G., Taylor M. R. Mutations associated with variant phenotypes in ataxia-telangiectasia. Am J Hum Genet. 1996 Aug;59(2):320–330. [PMC free article] [PubMed] [Google Scholar]
  25. Orita M., Suzuki Y., Sekiya T., Hayashi K. Rapid and sensitive detection of point mutations and DNA polymorphisms using the polymerase chain reaction. Genomics. 1989 Nov;5(4):874–879. doi: 10.1016/0888-7543(89)90129-8. [DOI] [PubMed] [Google Scholar]
  26. Padgett R. A., Grabowski P. J., Konarska M. M., Seiler S., Sharp P. A. Splicing of messenger RNA precursors. Annu Rev Biochem. 1986;55:1119–1150. doi: 10.1146/annurev.bi.55.070186.005351. [DOI] [PubMed] [Google Scholar]
  27. Ruttledge M. H., Andermann A. A., Phelan C. M., Claudio J. O., Han F. Y., Chretien N., Rangaratnam S., MacCollin M., Short P., Parry D. Type of mutation in the neurofibromatosis type 2 gene (NF2) frequently determines severity of disease. Am J Hum Genet. 1996 Aug;59(2):331–342. [PMC free article] [PubMed] [Google Scholar]
  28. Savitsky K., Bar-Shira A., Gilad S., Rotman G., Ziv Y., Vanagaite L., Tagle D. A., Smith S., Uziel T., Sfez S. A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science. 1995 Jun 23;268(5218):1749–1753. doi: 10.1126/science.7792600. [DOI] [PubMed] [Google Scholar]
  29. Savitsky K., Platzer M., Uziel T., Gilad S., Sartiel A., Rosenthal A., Elroy-Stein O., Shiloh Y., Rotman G. Ataxia-telangiectasia: structural diversity of untranslated sequences suggests complex post-transcriptional regulation of ATM gene expression. Nucleic Acids Res. 1997 May 1;25(9):1678–1684. doi: 10.1093/nar/25.9.1678. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Savitsky K., Sfez S., Tagle D. A., Ziv Y., Sartiel A., Collins F. S., Shiloh Y., Rotman G. The complete sequence of the coding region of the ATM gene reveals similarity to cell cycle regulators in different species. Hum Mol Genet. 1995 Nov;4(11):2025–2032. doi: 10.1093/hmg/4.11.2025. [DOI] [PubMed] [Google Scholar]
  31. Schwarze U., Goldstein J. A., Byers P. H. Splicing defects in the COL3A1 gene: marked preference for 5' (donor) spice-site mutations in patients with exon-skipping mutations and Ehlers-Danlos syndrome type IV. Am J Hum Genet. 1997 Dec;61(6):1276–1286. doi: 10.1086/301641. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Shapiro M. B., Senapathy P. RNA splice junctions of different classes of eukaryotes: sequence statistics and functional implications in gene expression. Nucleic Acids Res. 1987 Sep 11;15(17):7155–7174. doi: 10.1093/nar/15.17.7155. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Stankovic T., Kidd A. M., Sutcliffe A., McGuire G. M., Robinson P., Weber P., Bedenham T., Bradwell A. R., Easton D. F., Lennox G. G. 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. 1998 Feb;62(2):334–345. doi: 10.1086/301706. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Steingrimsdottir H., Rowley G., Dorado G., Cole J., Lehmann A. R. Mutations which alter splicing in the human hypoxanthine-guanine phosphoribosyltransferase gene. Nucleic Acids Res. 1992 Mar 25;20(6):1201–1208. doi: 10.1093/nar/20.6.1201. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Swift M., Morrell D., Massey R. B., Chase C. L. Incidence of cancer in 161 families affected by ataxia-telangiectasia. N Engl J Med. 1991 Dec 26;325(26):1831–1836. doi: 10.1056/NEJM199112263252602. [DOI] [PubMed] [Google Scholar]
  36. Telatar M., Teraoka S., Wang Z., Chun H. H., Liang T., Castellvi-Bel S., Udar N., Borresen-Dale A. L., Chessa L., Bernatowska-Matuszkiewicz E. Ataxia-telangiectasia: identification and detection of founder-effect mutations in the ATM gene in ethnic populations. Am J Hum Genet. 1998 Jan;62(1):86–97. doi: 10.1086/301673. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Telatar M., Wang Z., Udar N., Liang T., Bernatowska-Matuszkiewicz E., Lavin M., Shiloh Y., Concannon P., Good R. A., Gatti R. A. Ataxia-telangiectasia: mutations in ATM cDNA detected by protein-truncation screening. Am J Hum Genet. 1996 Jul;59(1):40–44. [PMC free article] [PubMed] [Google Scholar]
  38. Uziel T., Savitsky K., Platzer M., Ziv Y., Helbitz T., Nehls M., Boehm T., Rosenthal A., Shiloh Y., Rotman G. Genomic Organization of the ATM gene. Genomics. 1996 Apr 15;33(2):317–320. doi: 10.1006/geno.1996.0201. [DOI] [PubMed] [Google Scholar]
  39. Vorechovský I., Rasio D., Luo L., Monaco C., Hammarström L., Webster A. D., Zaloudik J., Barbanti-Brodani G., James M., Russo G. The ATM gene and susceptibility to breast cancer: analysis of 38 breast tumors reveals no evidence for mutation. Cancer Res. 1996 Jun 15;56(12):2726–2732. [PubMed] [Google Scholar]
  40. Wright J., Teraoka S., Onengut S., Tolun A., Gatti R. A., Ochs H. D., Concannon P. A high frequency of distinct ATM gene mutations in ataxia-telangiectasia. Am J Hum Genet. 1996 Oct;59(4):839–846. [PMC free article] [PubMed] [Google Scholar]

Articles from American Journal of Human Genetics are provided here courtesy of American Society of Human Genetics

RESOURCES