Abstracts
Résumé
L’identification des mutations à l’origine de maladies génétiques chez l’homme a pris ces dernières années un essor considérable. Il est devenu possible d’établir le spectre des mutations délétères pour une maladie génétique donnée, et des bases de données internationales sont aujourd’hui accessibles via le réseau Internet. Le diagnostic génotypique des maladies héréditaires occupe actuellement une place prépondérante en matière de conseil génétique et de diagnostic prénatal. La connaissance du type de mutation délétère et des mécanismes en cause est essentielle pour déterminer la stratégie de diagnostic moléculaire adaptée à chaque situation. Cet article a pour objectif de présenter les différents types de mutations responsables de maladies génétiques (substitutions nucléotidiques, délétions ou insertions de petite taille, mutations dynamiques, grands remaniements…) et de récapituler les connaissances actuelles concernant les mécanismes moléculaires à l’origine de ces mutations. Leurs conséquences sur l’expression du gène (transcription et maturation du transcrit) et sur la fonction de la protéine sont également abordées dans cet article.
Summary
The identification of mutations leading to human genetic diseases has grown into an intensive research field during the last few years. Through novel DNA analysis progress, it is now possible to determine the mutational spectrum for a given genetic disease and international databases are now available online. Genetic diagnosis of hereditary diseases has become an essential tool in genetic counselling and prenatal diagnosis. The knowledge of the deleterious mutation type and the molecular associated mechanism is fundamental in order to devise the optimal molecular diagnosis strategy. This review aims to present the various mutation categories involved in genetic diseases (single base-pair substitutions, small deletions or insertions, dynamic mutations, gross DNA lesions…) and to summarize our current knowledge about the main molecular mechanisms responsible for these mutations. Their deleterious consequences on gene expression, including transcription and transcript maturation, and protein loss or gain of function are also discussed in this review.
Appendices
Références
- 1. Hamosh A, Scott AF, Amberger J, et al. Online Mendelian inheritance in man (OMIM). Hum Mutat 2000 ; 15 : 57-61.
- 2. Stenson PD, Ball EV, Mort M, et al. Human gene mutation database (HGMD) : 2003 update. Hum Mutat 2003 ; 21 : 577-81.
- 3. Krawczak M, Ball EV, Cooper DN. Neighboring-nucleotide effects on the rates of germ-line single-base-pair substitution in human genes. Am J Hum Genet 1998 ; 63 : 474-88.
- 4. Brown LY, Brown SA. Alanine tracts : the expanding story of human illness and trinucleotide repeats. Trends Genet 2004 ; 20 : 51-8.
- 5. Lalioti MD, Scott HS, Buresi C, et al. Dodecamer repeat expansion in cystatin B gene in progressive myoclonus epilepsy. Nature 1997 ; 386 : 847-51.
- 6. Matsuura T, Yamagata T, Burgess DL, et al. Large expansion of the ATTCT pentanucleotide repeat in spinocerebellar ataxia type 10. Nat Genet 2000 ; 26 : 191-4.
- 7. Liquori CL, Ricker K, Moseley ML, et al. Myotonic dystrophy type 2 caused by a CCTG expansion in intron 1 of ZNF9. Science 2001 ; 293 : 816-7.
- 8. Albrecht A, Mundlos S. The other trinucleotide repeat : polyalanine expansion disorders. Curr Opin Genet Dev 2005 ; 15 : 285-93.
- 9. Warren ST. Polyalanine expansion in synpolydactyly might result from unequal crossing-over of HOXD13. Science 1997 ; 275 : 408-9.
- 10. Emanuel BS, Shaikh TH. Segmental duplications : an expanding role in genomic instability and disease. Nat Rev Genet 2001 ; 791-800.
- 11. Shaw CJ, Lupski JR. Implications of the human genome architecture for rearrangement-based disorders : the genomic basis of disease. Hum Mol Genet 2004 ; 13 : 57-64.
- 12. Abeysinghe SS, Chuzhanova N, Krawczak M, et al. Translocation and gross deletion breakpoints in human inherited disease and cancer I : nucleotide composition and recombination-associated motifs. Hum Mutat 2003 ; 22 : 229-44.
- 13. Chuzhanova N, Abeysinghe SS, Krawczak M, et al. Translocation and gross deletion breakpoints in human inherited disease and cancer II : potential involvement of repetitive sequence elements in secondary structure formation between DNA ends. Hum Mutat 2003 ; 22 : 245-51.
- 14. Kazazian HH Jr, Wrong C, Youssoufian H, et al. Haemophilia A resulting from de novo onsertion of L1 sequences represents a novel mechanism for mutation in man. Nature 1988 ; 332 : 164-6.
- 15. Wallace MR, Andersen LB, Saulino AM, et al. A de novo Alu insertion results in neurofibromatosis type 1. Nature 1991 ; 353 : 864-6.
- 16. Deininger PL, Batzer MA. Mammalian retroelements. Genome Res 2002 ; 12 : 1455-65.
- 17. Jeffreys AJ, Tamaki K, MacLeod A, et al. Complex gene conversion events in germline mutation at human minisatellites. Nat Genet 1994 ; 6 : 136-45.
- 18. Spence JE, Perciaccante RG, Greig GM, et al. Uniparental disomy as a mechanism for human genetic disease. Am J Hum Genet 1988 ; 42 : 217-26.
- 19. Surani MA. Genetics : immaculate misconception. Nature 2002 ; 416 : 491-3.
- 20. Fisher RA, Hodges MD, Newlands ES. Familial recurrent hydatidiform mole : a review. J Reprod Med 2004 ; 49 : 595-601.
- 21. Goriely A, McVean GA, van Pelt AM, et al. Gain-of-function amino acid substitutions drive positive selection of FGFR2 mutations in human spermatogonia. Proc Natl Acad Sci USA 2005 ; 102 : 6051-6.
- 22. Tufarelli C, Stanley JA, Garrick D, et al. Transcription of antisense RNA leading to gene silencing and methylation as a novel cause of human genetic disease. Nat Genet 2003 ; 34 : 157-65.
- 23. Weaving LS, Ellaway CJ, Gecz J, Christodoulou J. Rett syndrome : clinical review and genetic update. J Med Genet 2005 ; 42 : 1-7.
- 24. Ranum LP, Day JW. Myotonic dystrophy : RNA pathogenesis comes into focus. Am J Hum Genet 2004 ; 74 : 793-804.
- 25. Wijmenga C, Hewitt JE, Sandkuijl LA, et al. Chromosome 4q DNA rearrangements associated with facioscapulohumeral muscular dystrophy. Nat Genet 1992 ; 2 : 26-30.
- 26. van der Maarel SM, Frants RR. The D4Z4 repeat-mediated pathogenesis of facioscapulohumeral muscular dystrophy. Am J Hum Genet 2005 ; 76 : 375-86.
- 27. Gabellini D, Green MR, Tupler R. Inappropriate gene activation in FSHD : a repressor complex binds a chromosomal repeat deleted in dystrophic muscle. Cell 2002 ; 110 : 339-48.
- 28. Winokur ST, Chen YW, Masny PS, et al. Expression profiling of FSHD muscle supports a defect in specific stages of myogenic differentiation. Hum Mol Genet 2003 ; 12 : 2895-907.
- 29. Jiang G, Yang F, van Overveld PG, et al. Testing the position-effect variegation hypothesis for facioscapulohumeral muscular dystrophy by analysis of histone modification and gene expression in subtelomeric 4q. Hum Mol Genet 2003 ; 12 : 2909-21.
- 30. Masny PS, Bengtsson U, Chung SA, et al. Localization of 4q35.2 to the nuclear periphery : is FSHD a nuclear envelope disease? Hum Mol Genet 2004 ; 13 : 1857-71.
- 31. Houdayer C, Stoppa-Lyonnet D. Transcriptional abnormalities and genetic testing. Med Sci(Paris) 2005 ; 21 : 170-4.
- 32. Cartegni L, Chew SL, Krainer AR. Listening to silence and understanding nonsense : exonic mutations that affect splicing. Nat Rev Genet 2002 ; 3 : 285-98.
- 33. Higgs DR, Goodbourn SE, Lamb J, et al. Alpha-thalassaemia caused by a polyadenylation signal mutation. Nature 1983 ; 306 : 398-400.
- 34. Lejeune F, Maquat LE. Mechanistic links between nonsense-mediated mRNA decay and pre-mRNA splicing in mammalian cells. Curr Opin Cell Biol 2005 ; 17 : 309-15.
- 35. Conti E, Izaurralde E. Nonsense-mediated mRNA decay : molecular insights and mechanistic variations across species. Curr Opin Cell Biol 2005 ; 17 : 316-25.
- 36. Inoue K, Khajavi M, Ohyama T, et al. Molecular mechanism for distinct neurological phenotypes conveyed by allelic truncating mutations. Nat Genet 2004 ; 36 : 361-9.
- 37. Vogt G, Chapgier A, Yang K, et al. Gains of glycosylation comprise an unexpectedly large group of pathogenic mutations. Nat Genet 2005 ; 37 : 692-700.
- 38. Hobbs HH, Brown MS, Goldstein JL. Molecular genetics of the LDL receptor gene in familial hypercholesterolemia. Hum Mutat 1992 ; 1 : 445-66.
- 39. Notaro R, Afolayan A, Luzzatto L. Human mutations in glucose 6-phosphate dehydrogenase reflect evolutionary history. FASEB J 2000 ; 14 : 485-94.
- 40. Gajko-Galicka A. Mutations in type I collagen genes resulting in osteogenesis imperfecta in humans. Acta Biochim Pol 2002 ; 49 : 433-41.
- 41. Naski MC, Wang Q, Xu J, Ornitz DM. Graded activation of fibroblast growth factor receptor 3 by mutations causing achondroplasia and thanatophoric dysplasia. Nat Genet 1996 ; 13 : 233-7.
- 42. Owen MC, Brennan SO, Lewis JH, Carrell RW. Mutation of antitrypsin to antithrombin. alpha 1-antitrypsin Pittsburgh (358 Met leads to Arg), a fatal bleeding disorder. N Engl J Med 1983 ; 309 : 694-8.
- 43. Landles C, Bates GP. Huntingtin and the molecular pathogenesis of Huntington’s disease. Fourth in molecular medicine review series. EMBO Rep 2004 ; 5 : 958-63.
- 44. Sasaki Y, Shimotake T, Go S, Iwai N. Total thyroidectomy for hereditary medullary thyroid carcinoma 12 years after correction of Hirschsprung’s disease. Eur J Surg 2001 ; 167 : 467-9.
- 45. Clain J, Lehmann-Che J, Dugueperoux I, et al. Misprocessing of the CFTR protein leads to mild cystic fibrosis phenotype. Hum Mutat 2005 ; 25 : 360-71.
- 46. Monplaisir N, Merault G, Poyart C, et al. Hemoglobin S Antilles : a variant with lower solubility than hemoglobin S and producing sickle cell disease in heterozygotes. Proc Natl Acad Sci USA 1986 ; 83 : 9363-7.
- 47. Grady WM. Genomic instability and colon cancer. Cancer Metastasis Rev 2004 ; 23 : 11-27.
- 48. Dermitzakis ET, Reymond A, Antonarakis SE. Conserved non-genic sequences - an unexpected feature of mammalian genomes. Nat Rev Genet 2005 ; 6 : 151-7.