Functional analysis of a large set of brca2 exon 7 variants highlights the predictive value of hexamer scores in detecting alterations of exonic splicing regulatory elements

Human Mutation

Volumn 34, Issue 11, 2013, Pages 1547-1557

  Di Giacomo, Daniela ^a,b   Gaildrat, Pascaline ^a   Abuli, Anna ^a,c   Abdat, Julie ^a   Frébourg, Thierry ^a,d   Tosi, Mario ^a   Martins, Alexandra ^a  

^a UNIVERSITY OF ROUEN   (France)

^b UNIVERSITY OF L'AQUILA   (Italy)

^c UNIVERSITY OF BARCELONA   (Spain)

^d ROUEN UNIVERSITY HOSPITAL   (France)

Author keywords

Bioinformatics predictions; BRCA2; Hereditary breast and ovarian cancer; RNA splicing regulation

Indexed keywords

BRCA2 PROTEIN;

5' UNTRANSLATED REGION; ARTICLE; BIOINFORMATICS; BREAST CANCER; CONTROLLED STUDY; EXON; EXON SKIPPING; FEMALE; GENE FREQUENCY; GENE IDENTIFICATION; GENE MUTATION; GENETIC VARIABILITY; HIGH THROUGHPUT SEQUENCING; HUMAN; HUMAN CELL; NUCLEOTIDE SEQUENCE; OVARY CANCER; PREDICTIVE VALUE; PRIORITY JOURNAL; REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION; RNA ANALYSIS; RNA SPLICING; SITE DIRECTED MUTAGENESIS; SPLICING DEFECT; TRANSLATION INITIATION;

BIOINFORMATICS PREDICTIONS; BRCA2; HEREDITARY BREAST AND OVARIAN CANCER; RNA SPLICING REGULATION;

AMINO ACID SUBSTITUTION; BASE SEQUENCE; BRCA2 PROTEIN; CHROMOSOME MAPPING; COMPUTATIONAL BIOLOGY; EXONS; GENE ORDER; GENETIC VARIATION; HUMANS; MUTATION; REGULATORY SEQUENCES, NUCLEIC ACID; RNA PRECURSORS; RNA SPLICE SITES; RNA SPLICING;

EID: 84885434679     PISSN: 10597794     EISSN: 10981004     Source Type: Journal    
DOI: 10.1002/humu.22428     Document Type: Article

References (35)

1. Barash Y, Calarco JA, Gao W, Pan Q, Wang X, Shai O, Blencowe BJ, Frey BJ. 2010. Deciphering the splicing code. Nature 465:53-59.
2. Biswas K, Das R, Alter BP, Kuznetsov SG, Stauffer S, North SL, Burkett S, Brody LC, Meyer S, Byrd RA, Sharan SK. 2011. A comprehensive functional characterization of BRCA2 variants associated with Fanconi anemia using mouse ES cell-based assay. Blood 118:2430-2442.
3. Caputo S, Benboudjema L, Sinilnikova O, Rouleau E, Béroud C, Lidereau R; French BRCA GGC Consortium. 2012. Description and analysis of genetic variants in French hereditary breast and ovarian cancer families recorded in the UMD-BRCA1/BRCA2 databases. Nucleic Acids Res 40:D992-D1002.
4. Cartegni L, Chew SL, Krainer AR. 2002. Listening to silence and understanding nonsense: exonic mutations that affect splicing. Nat Rev Genet 3:285-298.
5. Cartegni L, Wang J, Zhu Z, Zhang MQ, Krainer AR. 2003. ESEfinder: a web resource to identify exonic splicing enhancers. Nucleic Acids Res 31:3568-3571.
6. Chasin LA. 2007. Searching for splicing motifs. Adv Exp Med Biol 623:85-106.
7. Colombo M, De Vecchi G, Caleca L, Foglia C, Ripamonti CB, Ficarazzi F, Barile M, Varesco L, Peissel B, Manoukian S, Radice P. 2013. Comparative in vitro and in silico analyses of variants in splicing regions of BRCA1 and BRCA2 genes and characterization of novel pathogenic mutations. PLoS ONE 8:e57173.
8. De Conti L, Baralle M, Buratti E. 2013. Exon and intron definition in pre-mRNA splicing. Wiley Interdiscip Rev RNA 4:49-60.
9. Doktor TK, Schroeder LD, Vested A, Palmfeldt J, Andersen HS, Gregersen N, Andresen BS. 2011. SMN2 exon 7 splicing is inhibited by binding of hnRNP A1 to a common ESS motif that spans the 3' splice site. Hum Mutat 32:220-230.
10. Fairbrother WG, Yeh RF, Sharp PA, Burge CB. 2002. Predictive identification of exonic splicing enhancers in human genes. Science 297:1007-1013.
11. Flanigan KM, Dunn DM, von Niederhausern A, Soltanzadeh P, Howard MT, Sampson JB, Swoboda KJ, Bromberg MB, Mendell JR, Taylor LE, Anderson CB, Pestronk A, et al. 2011. Nonsense mutation-associated Becker muscular dystrophy: interplay between exon definition and splicing regulatory elements within the DMD gene. Hum Mutat 32:299-308.
12. Gaildrat P, Krieger S, Thery JC, Killian A, Rousselin A, Berthet P, Frebourg T, Hardouin A, Martins A, Tosi M. 2010a. The BRCA1 c.5434C>G (p.Pro1812Ala) variant induces a deleterious exon 23 skipping by affecting exonic splicing regulatory elements. J Med Genet 47:398-403.
13. Gaildrat P, Killian A, Martins A, Tournier I, Frébourg T, Tosi M. 2010b. Use of splicing reporter minigene assay to evaluate the effect on splicing of unclassified genetic variants. Methods Mol Biol 653:249-257.
14. Gaildrat P, Krieger S, Di Giacomo D, Abdat J, Révillion F, Caputo S, Vaur D, Jamard E, Bohers E, Ledemeney D, Peyrat JP, Houdayer C, et al. 2012. Multiple sequence variants of BRCA2 exon 7 alter splicing regulation. J Med Genet 49:609-617.
15. Goren A, Kim E, Amit M, Vaknin K, Kfir N, Ram O, Ast G. 2010. Overlapping splicing regulatory motifs-combinatorial effects on splicing. Nucleic Acids Res 38:3318-3327.
16. Ho SN, Hunt HD, Horton RM, Pullen JK, Pease LR. 1989. Site-directed mutagenesis by overlap extension using the polymerase chain reaction. Gene 77:51-59.
17. Houdayer C, Caux-Moncoutier V, Krieger S, Barrois M, Bonnet F, Bourdon V, Bronner M, Buisson M, Coulet F, Gaildrat P, Lefol C, Léone M, et al. 2012. Guidelines for splicing analysis in molecular diagnosis derived from a set of 327 combined in silico/in vitro studies on BRCA1 and BRCA2 variants. Hum Mutat 33:1228-1238.
18. Ke S, Shang S, Kalachikov SM, Morozova I, Yu L, Russo JJ, Ju J, Chasin LA. 2011. Quantitative evaluation of all hexamers as exonic splicing elements. Genome Res 21:1360-1374.
19. Pagani F, Stuani C, Tzetis M, Kanavakis E, Efthymiadou A, Doudounakis S, Casals T, Baralle FE. 2003. New type of disease causing mutations: the example of the composite exonic regulatory elements of splicing in CFTR exon 12. Hum Mol Genet 12:1111-1120.
20. Pettigrew CA, Wayte N, Wronski A, Lovelock PK, Spurdle AB, Brown MA. 2008. Colocalisation of predicted exonic splicing enhancers in BRCA2 with reported sequence variants. Breast Cancer Res Treat 110:227-234.
21. Raponi M, Kralovicova J, Copson E, Divina P, Eccles D, Johnson P, Baralle D, Vorechovsky I. 2011. Prediction of single-nucleotide substitutions that result in exon skipping: identification of a splicing silencer in BRCA1 exon 6. Hum Mutat 32:436-444.
22. Raponi M, Douglas AG, Tammaro C, Wilson DI, Baralle D. 2012. Evolutionary constraint helps unmask a splicing regulatory region in BRCA1 exon 11. PLoS One 7:e37255.
23. Sanz DJ, Acedo A, Infante M, Durán M, Pérez-Cabornero L, Esteban-Cardeñosa E, Lastra E, Pagani F, Miner C, Velasco EA. 2010. A high proportion of DNA variants of BRCA1 and BRCA2 is associated with aberrant splicing in breast/ovarian cancer patients. Clin Cancer Res 16:1957-1967.
24. Shapiro MB, Senapathy P. 1987. RNA splice junctions of different classes of eukaryotes: sequence statistics and functional implications in gene expression. Nucleic Acids Res 15:7155-7174.
25. Spurdle AB, Couch FJ, Hogervorst FB, Radice P, Sinilnikova OM; IARC Unclassified Genetic Variants Working Group. 2008. Prediction and assessment of splicing alterations: implications for clinical testing. Hum Mutat 29:1304-13.
26. Théry JC, Krieger S, Gaildrat P, Révillion F, Buisine MP, Killian A, Duponchel C, Rousselin A, Vaur D, Peyrat JP, Berthet P, Frébourg T, et al. 2011. Contribution of bioinformatics predictions and functional splicing assays to the interpretation of unclassified variants of the BRCA genes. Eur J Hum Genet 19:1052-1058.
27. Tournier I, Vezain M, Martins A, Charbonnier F, Baert-Desurmont S, Olschwang S, Wang Q, Buisine MP, Soret J, Tazi J, Frébourg T, Tosi M. 2008. A large fraction of unclassified variants of the mismatch repair genes MLH1 and MSH2 is associated with splicing defects. Hum Mutat 29:1412-1424.
28. Vallée MP, Francy TC, Judkins MK, Babikyan D, Lesueur F, Gammon A, Goldgar DE, Couch FJ, Tavtigian SV. 2012. Classification of missense substitutions in the BRCA genes: a database dedicated to Ex-UVs. Hum Mutat 33:22-28.
29. Vezain M, Saugier-Veber P, Goina E, Touraine R, Manel V, Toutain A, Fehrenbach S, Frébourg T, Pagani F, Tosi M, Martins A. 2010. A rare SMN2 variant in a previously unrecognized composite splicing regulatory element induces exon 7 inclusion and reduces the clinical severity of spinal muscular atrophy. Hum Mutat 31:E1110-E1125.
30. Vezain M, Gérard B, Drunat S, Funalot B, Fehrenbach S, N'guyen-Viet V, Vallat JM, Frébourg T, Tosi M, Martins A, Saugier-Veber P. 2011. A leaky splicing mutation affecting SMN1 exon 7 inclusion explains an unexpected mild case of spinal muscular atrophy. Hum Mutat 32:989-994.
31. Vreeswijk MP, Kraan JN, van der Klift HM, Vink GR, Cornelisse CJ, Wijnen JT, Bakker E, van Asperen CJ, Devilee P. 2008. Intronic variants in BRCA1 and BRCA2 that affect RNA splicing can be reliably selected by splice-site prediction programs. Hum Mutat 30:107-114.
32. Walker LC, Whiley PJ, Couch FJ, Farrugia DJ, Healey S, Eccles DM, Lin F, Butler SA, Goff SA, Thompson BA, Lakhani SR, Da Silva LM, et al. 2010. Detection of splicing aberrations caused by BRCA1 and BRCA2 sequence variants encoding missense substitutions: implications for prediction of pathogenicity. Hum Mutat 31:E1484-E1505.
33. Wu Y, Zhang Y, Zhang J. 2005. Distribution of exonic splicing enhancer elements in human genes. Genomics 86:329-336.
34. Wang Z, Burge CB. 2008. Splicing regulation: from a parts list of regulatory elements to an integrated splicing code. RNA 14:802-813.
35. Whiley PJ, Pettigrew CA, Brewster BL, Walker LC; kConFab Investigators, Spurdle AB, Brown MA. 2010. Effect of BRCA2 sequence variants predicted to disrupt exonic splice enhancers on BRCA2 transcripts. BMC Med Genet 11:80.