title: Variant ataxia telangiectasia: clinical and molecular findings and evaluation of radiosensitive phenotypes in a patient and relatives.
abstract: Variant ataxia telangiectasia (A-T) may be an underdiagnosed entity. We correlate data from radiosensitivity and kinase assays with clinical and molecular data from a patient with variant A-T and relatives. The coding region of ATM was sequenced. To evaluate the functional effect of the mutations, we performed kinase assays and developed a novel S-G2 micronucleus test. Our patient presented with mild dystonia, moderately dysarthric speech, increased serum α-fetoprotein but no ataxia nor telangiectasias, no nystagmus or oculomotor dyspraxia. She has a severe IgA deficiency, but does not have recurrent infections. She is compound heterozygote for ATM c.8122G>A (p.Asp2708Asn) and c.8851-1G>T, leading to in frame loss of 63 nucleotides at the cDNA level. A trace amount of ATM protein is translated from both alleles. Residual kinase activity is derived only from the p.Asp2708Asn allele. The conventional G0 micronucleus test, based on irradiation of resting lymphocytes, revealed a radiosensitive phenotype for the patient, but not for the heterozygous relatives. As ATM is involved in homologous recombination and G2/M cell cycle checkpoint, we optimized an S-G2 micronucleus assay, allowing to evaluate micronuclei in lymphocytes irradiated in the S and G2 phases. This test showed increased radiosensitivity for both the patient and the heterozygous carriers. Intriguingly, heterozygous carriers of c.8851-1G>T (mutation associated with absence of kinase activity) showed a stronger radiosensitive phenotype with this assay than heterozygous carriers of p.Asp2708Asn (mutation associated with residual kinase activity). The modified S-G2 micronucleus assay provided phenotypic insight into complement the diagnosis of this atypical A-T patient.
authors: Center for Medical Genetics, Ghent University Hospital, De Pintelaan 185, 9000, Ghent, Belgium. kathleen.claes@ugent.be
authors: Kathleen
authors: K
authors: Claes
authors: Julie
authors: J
authors: Depuydt
authors: A Malcolm R
authors: AM
authors: Taylor
authors: James I
authors: JI
authors: Last
authors: Annelot
authors: A
authors: Baert
authors: Peter
authors: P
authors: Schietecatte
authors: Veerle
authors: V
authors: Vandersickel
authors: Bruce
authors: B
authors: Poppe
authors: Kim
authors: K
authors: De Leeneer
authors: Marc
authors: M
authors: D'Hooghe
authors: Anne
authors: A
authors: Vral
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution; D001260:Ataxia Telangiectasia / Q000235:genetics*; D064007:Ataxia Telangiectasia Mutated Proteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D001943:Breast Neoplasms / Q000235:genetics; D002110:Caffeine / Q000494:pharmacology; D002648:Child; D005091:Exons / Q000235:genetics; D005260:Female; D016195:G2 Phase; D006579:Heterozygote; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects / Q000528:radiation effects; D008297:Male; D015162:Micronucleus Tests; D020125:Mutation, Missense; D009386:Neoplastic Syndromes, Hereditary / Q000235:genetics; D009460:Neurologic Examination; D010375:Pedigree; D010641:Phenotype; D022821:RNA Splice Sites / Q000235:genetics; D011836:Radiation Tolerance / Q000235:genetics; D059767:Recombinational DNA Repair / Q000235:genetics; D018233:Rhabdomyosarcoma, Embryonal / Q000235:genetics; D016196:S Phase; D017422:Sequence Analysis, DNA
chemical_list: D022821:RNA Splice Sites; D002110:Caffeine; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins
references: Radiat Res. 1996 Jan;145(1):3-16
references: 8532833
references: Neurology. 2006 Jul 25;67(2):346-9
references: 16864838
references: Cancer Biol Ther. 2003 Jan-Feb;2(1):87-91
references: 12673126
references: Breast Cancer Res. 2011 Jul 25;13(4):R73
references: 21787400
references: J Biol Chem. 2011 Mar 18;286(11):9107-19
references: 21149446
references: Int J Radiat Biol. 1996 Aug;70(2):171-6
references: 8794846
references: Int J Radiat Biol. 2010 Jan;86(1):2-11
references: 20070210
references: Br J Cancer. 2004 Feb 23;90(4):866-73
references: 14970866
references: Int J Radiat Biol. 1999 Jan;75(1):1-10
references: 9972785
references: Mol Cell Biol. 2002 Feb;22(4):1049-59
references: 11809797
references: Br J Cancer. 2011 Aug 9;105(4):586-91
references: 21792198
references: Hum Mutat. 2009 Aug;30(8):1222-30
references: 19431188
references: Cancer Res. 2003 Dec 15;63(24):8717-25
references: 14695186
references: J Clin Invest. 2013 Mar;123(3):1335-42
references: 23454770
references: J Neurol. 2010 Oct;257(10):1738-40
references: 20480175
references: Eur J Med Genet. 2012 Jan;55(1):49-55
references: 21893220
references: Oncogene. 2004 Jan 22;23(3):824-34
references: 14737117
references: Am J Hum Genet. 1998 Feb;62(2):334-45
references: 9463314
references: Br Med Bull. 2006;77-78:71-85
references: 16971555
references: J Cell Biol. 2007 Mar 12;176(6):749-55
references: 17353355
references: Int J Radiat Biol. 1998 Sep;74(3):287-95
references: 9737532
references: J Natl Cancer Inst. 2010 Apr 7;102(7):475-83
references: 20305132
references: Eur J Paediatr Neurol. 2007 Nov;11(6):375-80
references: 17540590
references: Nature. 2003 Jan 30;421(6922):499-506
references: 12556884
references: Radiother Oncol. 2011 Oct;101(1):28-34
references: 22014898
references: Crit Rev Oncol Hematol. 2001 Feb;37(2):87-96
references: 11166582
references: Am J Hum Genet. 2009 Oct;85(4):427-46
references: 19781682
references: J Med Genet. 2002 Jan;39(1):57-61
references: 11826028
references: Int J Oncol. 2009 Nov;35(5):1223-30
references: 19787278
references: Hum Mutat. 2012 Mar;33(3):561-71
references: 22213089
references: J Pediatr. 2002 Jun;140(6):724-31
references: 12072877
references: Eur J Hum Genet. 2012 Mar;20(3):305-12
references: 22071889
references: J Neurol. 2008 Aug;255(8):1261-3
references: 18575927
references: Cancer Res. 2004 Jan 15;64(2):500-8
references: 14744762
references: Nature. 1978 Aug 3;274(5670):484-6
references: 672974
references: Cancer Res. 2000 Sep 1;60(17):4881-8
references: 10987302
references: Radiother Oncol. 2004 Sep;72(3):319-23
references: 15450731
references: Hum Mutat. 2006 Oct;27(10):1061
references: 16941484
references: EMBO J. 2006 Aug 9;25(15):3504-14
references: 16858402
references: Hum Genet. 1997 Dec;101(3):312-6
references: 9439660
references: Genomics. 1996 Apr 15;33(2):317-20
references: 8660985
references: Nat Rev Mol Cell Biol. 2008 Oct;9(10):759-69
references: 18813293
references: J Natl Cancer Inst. 1990 Jun 20;82(12):1050-4
references: 2348470
references: Am J Hum Genet. 1998 Mar;62(3):551-61
references: 9497252
references: Eur J Immunol. 2006 Jan;36(1):224-35
references: 16358361
references: Int J Radiat Biol. 1995 Aug;68(2):197-203
references: 7658145
references: Br J Cancer. 2001 Apr 6;84(7):892-6
references: 11286467
references: Neurology. 2009 Aug 11;73(6):430-7
references: 19535770
references: Mol Cell. 2004 Dec 3;16(5):715-24
references: 15574327
references: DNA Repair (Amst). 2004 Aug-Sep;3(8-9):889-900
references: 15279774
references: Int J Radiat Biol. 1994 Feb;65(2):175-84
references: 7907115
references: Ann Neurol. 2004 Jun;55(6):891-5
references: 15174027
references: Cancer Genet Cytogenet. 1994 Aug;76(1):43-6
references: 8076350