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Human Molecular Genetics Pages 145-150
Mutations revealed by sequencing the 5' half of the gene for ataxia telangiectasia
Introduction
Results
Discussion
Materials And Methods
   RACE and DNA sequencing
   Sequence analysis
   Mutation detection
Acknowledgements
References

Mutations revealed by sequencing the 5' half of the gene for ataxia telangiectasia

Mutations revealed by sequencing the 5 ' half of the gene for ataxia telangiectasia P. J. Byrd*, C. M. McConville, P. Cooper, J. Parkhill, T. Stankovic, G. M. McGuire, J. A. Thick and A. M. R. Taylor

Institute for Cancer Studies, The Medical School, University of Birmingham, Edgbaston, Birmingham, B15 2TJ, UKReceived October 2, 1995; Revised and Accepted October 26, 1995

Ataxia telangiectasia is a recessive disorder in which patients show a progressive cerebellar degeneration leading to ataxia, abnormal eye movements and deterioration of speech. Other features include ocular telangiectasia, high serum AFP levels, immunodeficiency, growth retardation and an increased predisposition to some tumours, particularly T cell leukaemia and lymphoma. We report the 1348 amino acid sequence of the N-terminal half of the A-T gene product which, together with the previously published C-terminal half, completes the sequence of the A-T protein. No homologies with other genes have been found within the N-terminal half of the A-T protein. We have also identified six mutations affecting the N-terminal half of the protein. One of these mutations was found to be associated with a haplotype that is common to four apparently unrelated families of Irish descent. All the patients so far examined for both A-T alleles were shown to be compound heterozygotes. None of these mutations affected a putative promoter region which may direct divergent transcription of both the A-T gene and a novel gene E14. The ability to recognise mutations across the entire coding sequence of the A-T gene provides a practical advantage to A-T families since a DNA based prenatal diagnosis will be possible in families where the mutations are identified irrespective of the level of radiosensitivity in these families.

INTRODUCTION

Patients with ataxia telangiectasia (A-T) show a remarkable range of clinical features affecting different tissues (1 ). The sine qua non for diagnosis of the disorder is a progressive cerebellar ataxia, resulting in patients being confined to a wheelchair by teenage, difficulties with speech and abnormal eye movements (1 ). A-T patients also have an increased predisposition to leukaemias and lymphomas (2 ) which is believed to arise from the increased numbers of chromosome translocations in the peripheral T cells, involving breakpoints in the T cell receptor genes (2 ). At the cellular level A-T patients have an enhanced sensitivity to ionizing radiation (3 ,4 ) and it has been suggested that they are defective in p53 accumulation after exposure to ionizing radiation (5 ,6 ). The A-T gene product appears to be important in several cellular functions all of which appear to have a role in maintaining genomic stability either by protecting the cell from induced damage to the DNA, or by preventing interlocus recombination between some immune system genes (7 ).

There is evidence of clinical, cellular and genetic heterogeneity in the disorder, so that the age of onset or the rate of progress of the disorder can be variable and the level of cellular radiosensitivity can also be markedly different from patient to patient (8 ). The observation of concordance of tumour type in A-T siblings (9 ,10 ) supports the contention that there is also variation in genetic predisposition to tumour development within the A-T population. Predisposition, say to T cell leukaemia is likely to result from the presence of a particular molecular defect which will in turn depend on the presence of particular mutations. Because of this observed heterogeneity in A-T it is expected that there will be many A-T mutations and the number and location of these is of some considerable interest.

There is increasing evidence that heterozygotes (estimated to be approximately 1% of the population of the USA) may have an elevated risk of breast cancer (11 ,12 ) and so again there is interest in the potential for screening sporadic breast cancer patients for the presence of a mutant A-T allele.

The A-T gene was recently identified, the 3' half of the transcript cloned and the amino acid sequence of this half of the A-T protein reported (13 ). This part of the gene was shown to have homology to several yeast and mammalian phosphatidylinositol-3' kinases involved in signal transduction, meiotic recombination and control of the cell cycle. More recently this part of the gene has been shown to have sequence and functional homology with the D. melanogaster mei-41 gene (14 ), the S. cerevisiae gene TEL1 (15 ), and human DNA protein kinase (16 ).

RESULTS

We have sequenced the 5' half of the A-T transcript which we isolated using a RACE approach. The 4.2 kb RACE product was found to have a long open reading frame (ORF) which, when conceptually translated (Fig. 1 ), matched the amino acid sequence of the 3' half of the A-T transcript [designated ATM (13 )], where it overlapped the published sequence. The RACE product encoded an additional 1348 amino acids 5' to the methionine which marked the start of the open reading frame in the ATM sequence, giving a total size for the A-T protein of 3056 amino acids. A protein database search revealed no significant matches to the amino acid sequence of the N-terminal half of the A-T protein reported here. No significant homologies were found between the N-terminal half of the A-T protein and the mei-41, TEL1 or MEC1 proteins previously shown to have homology with the C-terminal half of the gene. However a putative leucine zipper motif was identified at position 1217 (Fig. 1 ).


Figure 1. The amino acid sequence of the N-terminal half of the A-T protein. This sequence represents a translation of the long open reading frame in the 4.2 kb RACE product. The shaded box at the end of this polypeptide indicates the overlap with the published amino acid sequence of the C-terminal half of the A-T protein (13). The solid box indicates the putative leucine zipper, with leucine residues shaded.

To provide further confirmation that this RACE product was part of the A-T gene, we looked for mutations in A-T patients. cDNA was prepared from patient lymphoblastoid cell line RNA and was amplified by PCR using three pairs of overlapping primers (designated VI, VII and VIII) to cover completely the ORF contained within the 4.2 kb RACE product. Initial screening of amplification products on an agarose gel identified three patients for whom amplified cDNA fragments of altered size predicted deletions of at least 100 bp. Further screening using heteroduplex analysis or restriction endonuclease fingerprinting (17 ) of amplified cDNA identified a further three patients for whom altered fragment mobility on MDE gels was indicative of a different sequence alteration. All mutations were sequenced in order to determine their effect on protein structure (Table 1 ). In the majority of cases, the mutation is predicted to result in protein truncation. The initial mutation found with primer set VIII was in an Irish patient (51-6). Three additional Irish patients (4-4, 10-3 and 50-3; apparently unrelated) with the same haplotype as patient 51-6 for markers in the region of the A-T gene were also shown to have the same mutation, a 200 bp deletion in fragment VIII causing protein truncation after codon 880. This provides further evidence that the 5' RACE product is part of the A-T gene. It is of interest that for three of the patients in Table 1 , a mutation on the second allele has been identified in the 3' half of the gene (Table 1 ) and two of these mutations were identical.

Structural analysis of the RACE product showed that the 5' terminal 62 bp comprised a non-coding first exon with stop codons in all three reading frames (Fig. 2 ). The open reading frame encoding the A-T protein was found to initiate at the second ATG in exon 2. Attempts to RACE the A-T mRNA further in the 5' direction did not provide additional sequence information, suggesting that the 4.2 kb RACE product was essentially complete. A vectorette procedure (18 ) was used to capture and sequence 2 kb of genomic sequence flanking the 5' end of the RACE product. The initiation codon of the open reading frame of a novel expressed gene E14 that we had previously identified (Cooper, in preparation) was found 681 bp upstream of the initiation codon of the A-T gene. The A-T and E14 genes were found to be transcribed in opposite directions (Fig. 2 ). The sequence between the initiation codons of the A-T and E14 genes was found to comprise a CpG island containing >50% C+G and observed/expected CpG content of >0.6. This region might therefore represent a bidirectional promoter responsible for controlling the expression of both the A-T and E14 genes.

A search of the transcription factor binding site database TFD (19 ) predicted potential binding sites for a host of different factors in the putative promoter region. A cyclic AMP responsive element (CRE) (20 ) and sites for E4F1 (21 ) and E4TF1 (22 ) were predicted to overlap within a 14 bp sequence (Fig. 2 ). Two insulin responsive elements (IRE) (23 ) were found within two of four putative Sp1 sites which match the consensus Sp1 binding sequence (24 ) at eight or more out of ten bases. Two CCAAT boxes were predicted but no TATA homologies were found. The fact that Sp1 boxes are commonly found in bidirectional promoters in the absence of TATA motifs (25 -29 ), together with the other predicted transcription binding sites and CCAAT boxes, supports the prediction that the region between the first exons of the A-T and E14 genes represents a promoter with bidirectional properties.

Table 1 . Mutations in the ataxia telangiectasia gene
Patient no.

 Primer set

 DNA sequence change

 Protein alteration

  
First mutation identified in the 5' half of the A-T gene:
21-5

 VI

 deletion 166 bp

 frameshift codon 166

 truncation
28-3

 VI

 deletion 1 bp

 frameshift codon 214

 truncation
88-3

 VII

 deletion 2 bp

 frameshift codon 521

 truncation
95-3

 VII

 in frame deletion 126 bp

 deletion of codons 709-750

 deletion of 42 amino acids
79-3

 VII

 deletion 2 bp

 frameshift codon 762

 truncation
51-6

VIII

 deletion 200 bp

 frameshift codon 880

 truncation
4-4
10-3
50-3
Second mutation identified in the 3' half of the A-T gene for three patients:
21-5

 V

 in frame deletion 9 bp

 deletion of codons 2546-2548

 deletion of 3 amino acids
95-3

 IV

 insertion of 14 bp

 frameshift codon 2930

 truncation
51-6

 V

 in frame deletion 9 bp

 deletion of codons 2546-2548

 deletion of 3 amino acids
 

  

  

  

  
Codons 1-1348 represent the 5' portion of the A-T gene and codons 1349-3056, the 3' portion described by Savitsky et al (13). The second allele in patients 21-5 and 51-6 is identical to that described in patient AT2BR (13).

DISCUSSION


Figure 2. Sequence of the putative A-T promoter region. The sequence is genomic except for cDNA sequence downstream of the 5' end of the A-T RACE sequence. The first exon and part of the first intron of the E14 gene are shown in upper and lower cases respectively; the donor splice signal is boxed on the lower DNA strand. The first intron in the A-T gene, the sequence for which does not appear in the RACE cDNA, is indicated by a downward pointing open triangle. Translations of the ORFs are shown below and above the coding strands for the E14 and A-T genes respectively; arrows indicate the direction of transcription and translation. The 5' ends of the E14 cDNA and the A-T RACE product are indicated with angled arrows. Predicted Sp1 and CCAAT boxes are boxed and labelled. The shaded sequences within Sp1 boxes I and II indicate homologies with the insulin responsive element (IRE) CCCGCCTC (23). The dashed box identifies a 14 bp sequence that contains overlapping homologies for a cyclic AMP responsive element TGACGACA (20), transcription factor E4F1 TCGT(A/C)AC (21) and transcription factor E4TF1 CGGAAGTG (22) binding sites. The CG dinucleotides are highlighted in bold type to emphasise the CpG island.We have been able to sequence an additional 1348 amino acids of the A-T protein giving a total size for the protein of 3056 amino acids. Unlike the C -terminal half of the A-T gene no homologies were found between the N-terminal half of the A-T protein and the MEI 41, TEL1 or MEC1 proteins. A leucine zipper was identified in the N-terminal half of the A-T gene in a similar position (relative to the total length of the protein) to that in DNA-protein kinase although there was no significant homology between them. Hydrophobicity/hydrophilicity plots gave no indication that the A-T protein is membrane bound. There were numerous putative glycosylation, phosphorylation and myristoylation sites but no indication of the likely site or function in the nucleus. It was suggested, at one time, that DNA-PK might be a candidate for the A-T gene (30 ) since rodent or human cells lacking DNA-PK activity are hypersensitive to ionising radiation, are deficient in dsb repair and are defective in V(D)J recombination (16 ). Whilst we now know that the DNA-PK and A-T genes are different, the cellular and clinical phenotypes of this disorder are still compatible with a DNA-PK like activity for the A-T protein.

The patients described here are all compound heterozygotes for the A-T gene and our analysis of further patients (unpublished) across the whole of the A-T gene suggests that this will be the case for the vast majority of patients. Mutations were found in all three PCR products covering the N-terminal region of the protein and there does not appear to be a single hotspot for mutations in this region, although the fact that 3/6 mutations were clustered within a 170 amino acid segment of the protein, between residues 709 and 880, suggests that this may represent a functionally important part of the protein. This region, however, is outside the area of the putative leucine zipper motif. So far, we have been able to find second mutations in three of the patients described in Table 1 , all in the 3' half of the gene. The correlation between the presence of a recognisable haplotype for markers in the A-T gene region and the presence of a single mutation is interesting as there are several different haplotypes which can be recognised in A-T patients native to the British Isles. This suggests that some mutations will be more common than others and eventually it will be possible to make some estimate of the ages of the different mutations and gain some estimate of the rate of mutation of the A-T gene. The immediate practical consequence of the availability of the complete A-T gene coding sequence is for families contemplating the need for prenatal diagnosis for A-T.

The possibility that the A-T gene and the adjacent gene E14 share a bidirectional promoter is intriguing. Genes that share a bidirectional promoter may be involved in the same biochemical pathway or process (25 ,26 ), encode interacting gene products (27 ), or be unrelated by homology or function (28 ). The E14 gene shows low level expression across a wide variety of tissues (data not shown) and in addition the region between the first exons of the E14 and A-T genes has a high C+G content, both of which observations are compatible with E14 being a housekeeping gene. The functional relationship of the E14 gene, if any, to the A-T gene is at present unknown but there is a possibility that these genes may be co-ordinately regulated and perhaps involved in the same cellular processes.

MATERIALS AND METHODS

RACE and DNA sequencing

Placental poly A+ mRNA (1 [mu]g; Clontech) was reverse transcribed (Pharmacia Timesaver cDNA synthesis kit) using primer 7829 (5' CGA AGA ACA AAG GCC CAA GCT CCT CCT AAG 3') homologous to bases 583 to 612 of the ATM gene (13 ) (Genbank accession number U26455). An adaptor (Clontech Marathon cDNA kit) was ligated to the cDNA following second strand synthesis. Long range PCR was then performed using an adaptor specific primer (AP1; Clontech Marathon cDNA kit) and a primer 7828 (5' GCG ATG GAA AAT GAG GTG GAT TAG GAG CAG 3') homologous to bases 336 to 365 of the previously isolated 3'-terminal half of the ATM gene (13 ). PCR was performed using Expand PCR and buffer 1 (Boehringer Mannheim), annealing at 60oC (20 s), elongating at 68oC for 8 min for 10 cycles followed by 25 cycles in which the elongation time was extended by 20 s per cycle; a `hot start' was used and denaturation was at 94oC for 10 s in each cycle. The major amplification product (4.2 kb) was gel purified, diluted 250-fold and re-amplified using AP1 and 7828. Sequencing with the ATM gene specific primer 7828 confirmed that the 4.2 kb fragment was a 5' extension of the ATM sequence. Aliquots (10-20 ng) of the re-amplified gel purified 4.2 kb fragment were digested with twelve restriction enzymes that produce blunt ends i.e. AluI, Bst1107I, DraI, EcoRV, HaeIII, MscI, NruI, PvuII, RsaI, ScaI, SspI and StuI and ligated to a vectorette (18 ). PCR with AP1 and a vectorette specific primer produced amplified 5' terminal fragments that were sequenced with the vectorette primer (sequencing from the Clontech adaptor was unsuccessful). Using sequence generated from the ends of the 4.2 kb fragment internal primers were devised and a second round of vectorette PCR was performed using the vectorette libraries described above. Primers based on the new sequence were used in an additional round of vectorette PCR and the process was repeated until the complete sequence of the 4.2 kb fragment had been determined in both directions, multiple times. Putative 5' promoter region sequences were generated using primers near the 5' end of the 4.2 kb fragment in vectorette PCR on genomic DNA derived from the P1 clone 85N19 (31 ). The two primers used 8007 (5' GCA GAT CAT TAA GTA CTA GAC TCA TGG TTC AC 3') and 8021 (5' CTG TCA CTG CAC TCG GAA GGT CAA AGT AG 3') generated completely different vectorette products although the 5' end of one primer was separated by only 19 bp from the 3' end of the other, suggesting that they represented different exons. Primer 8194 (5' GGG AGT AGG TAG CTG CGT GGC TAA CGG 3') was used in vectorette PCR on 85N19 to capture genomic sequences that overlapped the splice donor side of the putative intron. The genomic sequences derived from the 8007 and 8194 genomic vectorette products confirmed the presence of an intron and identified consensus donor and acceptor splice sequences (data not shown). The genomic vectorette products generated with primer 8021, the primer nearest the 5' end of the RACE product, were sequenced and an overlapping contig of sequences was developed. Sequencing was performed using Applied Biosystems Prism Ready Reaction Dye Terminator Cycle Sequencing Kit and an Applied Biosystems 373A DNA sequencer. The sequence of the 5' half of the A-T gene transcript and the putative promoter region has been deposited in GenBank, accession number X91196.

Sequence analysis

The sequence of the 4.2 kb RACE product was assembled using the fragment assembly programs in GCG (Program manual for the Wisconsin Package, version 8, September 1994, Genetics computer group, 575 Science Drive, Madison, Wisconsin, USA 53711). The amino acid sequence of the longest ORF in the RACE product was used to search (a) a non-redundant protein database maintained by NCBI using the BLAST algorithm (32 ) and (b) the peptide motifs PROSITE database (33 ). Genomic DNA sequences overlapping the 5' end of the RACE product were used to search the TFD transcription factor DNA binding site database (19 ).

Mutation detection

RNA was prepared from A-T lymphoblastoid cell lines and first strand cDNA synthesized using a SuperScript preamplification system (Gibco BRL) with an oligo(dT) primer. PCR was carried out using this cDNA template and three sets of primers: (i) primer set VI: primer 8020: 5' GTG TTC TGA AAT TGT GAA CCA TGA GTC TAG T; primer 8149: 5' TGG TAT CTT CAT TAA AAA CCT GGT GAC AG (annealing temp, 57oC); (ii) primer set VII: primer 8085: 5' AGT AGA GGA AAG TAT TCT TCA GGA TTT CG; primer 8129: 5' CGT TTG CAT CAC TAA CAC TAC TAT CAG (annealing temp: 57oC); and (iii) primer set VIII: primer 8145: 5' GAG GTG GAG GAT CAG TCA TCC ATG AAT C; primer 7828: 5' GCG ATG GAA AAT GAG GTG GAT TAG GAG CAG (annealing temp: 58oC). Primers for the 3' half of the gene were kindly provided by Y. Shiloh. PCR products were purified using the QIAquick Spin Kit (QIAgen Ltd.) and analysed for mutations either by SSCP using the REF (restriction endonuclease fingerprinting) method of Liu and Sommer (17 ), or by heteroduplex analysis on MDE gels (FMC BioProducts). In the case of heteroduplex analysis three or more of the enzymes AluI, DdeI, HinfI, HaeIII, MboI and MnlI were used in individual digests. The use of several different enzyme digests increased the sensitivity of mutation detection and allowed accurate localization of mutations to within 150-200 bp. Appropriate cDNA segments were reamplified, gel purified and sequenced using an Applied Biosystems 373A DNA sequencer.

ACKNOWLEDGEMENTS

We thank the Cancer Research Campaign, the Wellcome Trust, the A-T Society of the U.K. the A-T Research and Support Trust and the A-T Medical Research Trust for their continued support. We would also like to thank Pieter de Jong for P1 clones and Alta Bioscience, University of Birmingham, for sequencing.

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*To whom correspondence should be addressed

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