Rozdíly v počtu CAG opakování mezi pohlavími a jejich korelace s klinickým obrazem u Huntingtonovy choroby
Autoři:
D. Zielonka 1; A. Niezgoda 2; M. Olejniczak 3; W. Krzyzosiak 3; J. Marcinkowski 1; W. Kozubski 2
Působiště autorů:
Department of Social Medicine, Poznan University of Medical Sciences, Poland
1; Department of Neurology, Poznan University of Medical Sciences, Poland
2; Laboratory of Cancer Genetics, Institute of Bioorganic Chemistry, Polish Academy of Sciences in Poznan, Poland
3
Vyšlo v časopise:
Cesk Slov Neurol N 2008; 71/104(6): 688-694
Kategorie:
Původní práce
Souhrn
Cíle:
Huntingtonova choroba (HD) je dědičná neurodegenerativní porucha. Vztah mezi progresí příznaků a počtem CAG opakování u zmutovaného genu IT15 nebyl prozatím z hlediska pohlaví probádán. Cílem bylo zjistit všechny korelace mezi počtem trinukleotidových repeticí CAG u genu IT15 a věkem nástupu HD, symptomy a progresí nemoci, jakož i případné rozdíly mezi výsledky v závislosti na pohlaví.
Materiál a metodika:
41 pacientů (23 žen a 18 mužů) s mutací způsobující HD se podrobilo neurologickému hodnocení podle Jednotné hodnotící škály Huntingtonovy choroby (Unified Huntington’s Disease Rating Scale, UHDRS). Počet CAG repetic na exonu 1 genu IT15 byl stanoven metodou amplifikace DNA pomocí polymerázové řetězové reakce (PCR) a porovnáním výsledného produktu se standardní DNA.
Výsledky:
Signifikantní korelace mezi výsledky na škále UHDRS, počtem CAG opakování a časem propuknutí choroby byly objeveny pouze u žen. Korelace mezi počtem CAG opakování a věkem nástupu nemoci byla objevena jak u žen, tak u mužů.
Závěr:
Výsledky naznačují korelaci mezi klinickým stavem pacientek s HD a délkou CAG repetice. To by mohlo souviset s přítomností dalšího faktoru u žen.
Klíčová slova:
CAG trinukleotidová opakování – Huntingtonova nemoc – UHDRS – pohlaví
Zdroje
1. Martin JB, Gusella JF. Huntington‘s disease. Pathogenesis and management. N Engl J Med 1986; 315(20): 1267–1276.
2. Zielonka D, de Mezer M, Niezgoda A, Reperowicz K, Krzyzosiak W, Kozubski W. Clinical picture of patients with Huntington‘s disease in relation to the number of trinucleotide CAG repeats in IT–15 gene. Neurol Neurochir Pol 2002; 36(5): 903–909.
3. Huntington Study Group. Uniform Huntington’s Disease Rating Scale: reliability and consistency. Mov Dis 1996; 11: 136–142.
4. Sharma KR, Romano JG, Ayyar DR, Rotta FT, Facca A, Sanchez-Ramos J. Sympathetic skin response and heart rate variability in patients with Huntington’s disease. Arch Neurol 1999; 56(10): 1248–1252.
5. Peel A, Rao R, Cottrell B, Hayden MR, Ellerby LM, Bredesen DE. Double–stranded RNA-depended protein kinase, PKR, binds preferentially to Huntington’s disease (HD) transcripts and is activated in HD tissue. Hum Mol Genet 2001; 10(15): 1531–1538.
6. Zielonka D, Reperowicz K, Murawa D, Krzyżosiak W, Kozubski W. Obraz kliniczny w kontekście badań genetycznych i neuroobrazowych u pacjentów z pląsawicą Huntingtona. Nowiny Lekarskie 2000; 3: 307–404.
7. Kendall M. A new measure of rank correlation. Biometrika 1938; 30: 81–89.
8. Congdon P. Bayesian Statistical Modelling. Chichester (UK): Wiley 2001: 429–430.
9. Lunn DJ, Thomas A, Best N, Spiegelhalter D. WinBUGS – a Bayesian modelling framework: concepts, structure, and extensibility. Stat Comput 2000; 10: 325–337.
10. Kieburtz K, MacDonald M, Shih C, Feigin A, Steinberg K, Bordwell K et al. Trinucleotide repeat length and progression of illness in Huntington‘s disease. J Med Genet 1994; 31(11): 872–874.
11. Claes S, Van Zand K, Legius E, Dom R, Malfroid M, Baro F et al. Correlations between triplet repeat expansion and clinical features in Huntington‘s disease. Arch Neurol 1995; 52(8): 749–753.
12. Benitez J, Fernandez E, Garcia Ruiz P, Robledo M, Ayuso C, Garcia Yebenes J. The gene responsible for Huntington‘s disease in Spanish families: its diagnostic value and the relation between trinucleotide expansion and the clinical characteristics. Rev Clin Esp 1994; 194(8): 591–593.
13. Feigin A, Kieburtz K, Bordwell K, Como P, Steinberg K, Sotack J et al. Functional decline in Huntington’s disease. Mov Disord 1995; 10(2): 211–214.
14. Siesling S, van Vugt J, Zwinderman KA, Kieburtz K, Roos R. Unified Huntington’s disease rating scale: a follow up. Mov Disord 1998; 13(6): 915–919.
15. Marder K, Zhao H, Myers RH, Cudkowicz M, Kayson E, Kieburtz K et al. Rate of functional decline in Huntington’s disease. Neurology 2000; 54(2): 452–458.
16. Squitieri F, Gellera C, Cannella M, Mariotti C, Cislaghi G, Rubinsztein DC et al. Homozygosity for CAG mutation in Huntington disease is associated with a more severe clinical course. Brain 2003; 126(4): 946–955.
17. Dürr A, Hahn-Barma V, Brice A, Pêcheux C, Dodé C, Feingold J. Homozygosity in Huntington‘s disease. J Med Genet 1999; 36(2): 172–173.
18. MacDonald M, Vonsattel J, Shrinidhi J, Couropmitree NN, Cupples LA, Bird ED et al. Evidence for the GluR6 gene associated with younger onset age of Huntington‘s disease. Neurology 1999; 53(6): 1330–1332.
19. de Rooij KE, de Koning Gans PA, Losekoot M, Bakker E, den Dunnen JT, Vegter-van der Vlis M et al. Borderline repeat expansion in Huntington‘s disease. Lancet 1993 11; 342(8885): 1491–1492.
20. Andresen JM, Gayán J, Cherny SS, Brocklebank D, Alkorta-Aranburu G, Addis EA. Replication of twelve association studies for Huntington‘s disease residual age of onset in large Venezuelan kindreds. J Med Genet 2007; 44(1): 44–50.
21. Arning L, Saft C, Wieczorek S, Andrich J, Kraus PH, Epplen JT. NR2A and NR2B receptor gene variations modify age at onset in Huntington’s disease in a sex-specific manner. Hum Genet 2007; 122(2): 175–182.
22. Kehoe P, Krawczak M, Harper PS, Owen MJ, Jones AL. Age of onset in Huntington disease: sex specific influence of apolipoprotein E genotype and normal CAG repeat length. J Med Genet 1999; 36(2): 108–111.
23. Saft C, Andrich JE, Brune N, Gencik M, Kraus PH, Przuntek H et al. Apolipoprotein E genotypes do not influence the age of onset in Huntington‘s disease. J Neurol Neurosurg Psychiatry 2004; 75(12): 1692–1696.
24. Squitieri F, Frati L, Ciarmiello A, Lastoria S, Quarrell O. Juvenile Huntington’s disease: Does a dosage-effect pathogenic mechanism differ from the classical adult disease? Mech of Ageing Dev 2006; 127(2): 208–212.
25. Židovská J, Klempíř J, Kebrdlová V, Uhrová T, Koblihová J, Anders M et al. Huntingtonova nemoc: zkušenosti s genetickým testováním v letech 1994–2005. Cesk Slov Neurol N 2007; 70/103(1): 72–77.
26. Andresen JM, Gayán J, Djoussé L, Roberts S, Brocklebank D, Cherny SS. The relationship between CAG repeat length and age of onset differs for Huntington‘s disease patients with juvenile onset or adult onset. Ann Hum Genet 2007;71(3): 295–301.
27. Seneca S, Fagnart D, Keymolen K, Lissens W, Hasaerts D, Debulpaep S et al. Early onset Huntington disease: a neuronal degeneration syndrome. Eur J Pediatr 2004; 163(12): 717–721.
28. Dorner JL, Miller BR, Barton SJ, Brock TJ, Rebec GV. Sex differences in behavior and striatal ascorbate release in the 140 CAG knock-in mouse model of Huntington‘s disease. Behav Brain Res 2007; 178(1): 90–97.
29. Kovtun I, Therneau T, McMurray C. Gender of the embryo contributes to CAG instability in transgenic mice containing a Huntington‘s disease gene. Hum Mol Genet 2000; 9(18): 2767–2775.
30. MacDonald ME, Barnes G, Srinidhi J, Duyao MP, Ambrose CM, Myers RH et al. Gametic but not somatic instability of CAG repeat length in Huntington‘s disease. J Med Genet 1993; 30(12): 982–986.
31. Zühlke C, Riess O, Bockel B, Lange H, Thies U. Mitotic stability and meiotic variability of the (CAG)n repeat in the Huntington’s disease gene. Hum Mol Genet 1993; 2(12): 2063–2067.
32. Leeflang E, Tavare S, Marjoram P, Neal CO, Srinidhi J, MacFarlane H et al. Analysis of germline mutation spectra at the Huntington‘s disease locus supports a mitotic mutation mechanism. Hum Mol Genet 1999; 8(2): 173–183.
33. Wexler NS, Lorimer J, Porter J, Gomez F, Moskowitz C, Shackell E et al. Venezuelan kindreds reveal that genetic and environmental factors modulate Huntington‘s disease age of onset. Proc Natl Acad Sci USA 2004; 101(10): 3498–3503.
34. Cannella M, Gellera C, Maglione V, Giallonardo P, Cislaghi G, Muglia M. The gender effect in juvenile Huntington disease patients of Italian origin. Am J Med Genet B Neuropsychiatr Genet 2004; 125B(1): 92–98.
35. Sánchez A, Mìla M, Castellvi-Bel S, Calopa M, Genis D, Jiménez D et al. Molecular analysis of the IT-15 gene in 79 Spanish families with Huntington‘s disease: diagnostic confirmation and presymptomatic diagnosis. Med Clin (Barc) 1997; 108(18): 687–690.
36. Vojvodić N, Culjković B, Romac S, Stojković O, Sternić N, Sokić D et al. Importance of the number of trinucleotide repeat expansions in the clinical manifestations of Huntington‘s chorea. Srp Arh Celok Lek 1998; 126(3–4): 77–82.
37. Snell R, MacMillan J, Cheadle J, Fenton I, Lazarou LP, Davies P et al. Relationship between trinucleotide repeat expansion and phenotypic variation in Huntington‘s disease. Nat Genet 1993; 4(4): 393–397.
38. Ranen NG, Stine OC, Abbott MH, Sherr M, Codori AM, Franz ML et al. Anticipation and instability of IT-15 (CAG)n repeats in parent‑offspring pairs with Huntington disease. Am J Hum Genet 1995; 57(3): 593–602.
39. Brandt J, Bylsma FW, Gross R, Stine OC, Ranen N, Roos CA. Trinucleotyde repeat length and clinical progression in Huntington’s disease. Neurology 1996; 46(2): 527–531.
40. Squitieri F, Cannella M, Simonelli M. CAG mutation effect on rate of progression in Huntington’s disease. Neurol Sci 2002; 23 (Suppl 2): S107–S108.
41. Illarioshkin SN, Igarashi S, Onodera O, Markova ED, Nikolskaya NN, Tanaka H et al. Trinucleotide repeat length and rate of progression of Huntington‘s disease. Ann Neurol 1994; 36(4): 630–635.
42. Paulsen JS, Langbehn DR, Stout JC, Aylward E, Ross CA, Nance M et al. Detection of Huntington‘s disease decades before diagnosis: the Predict-HD study. J Neurol Neurosurg Psychiatry 2008; 79(8): 874–880.
43. Pekmezovic T, Svetel M, Maric J, Dujmovic-Basuroski I, Dragasevic N, Keckarevic M et al. Survival of Huntington‘s disease patients in Serbia: longer survival in female patients. Eur J Epidemiol 2007; 22(8): 523–526.
Štítky
Dětská neurologie Neurochirurgie NeurologieČlánek vyšel v časopise
Česká a slovenská neurologie a neurochirurgie
2008 Číslo 6
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