ANALIZA POLIMORFIZMA RS34637584 U GENU LRRK2 KOD BOLESNIKA SA PARKINSONOVOM BOLEŠĆU

  • Boba Kotlica Student Medicinskog fakulteta, Univerzitet u Beogradu
  • Profesor Momčilo Ristanović Profesor
  • Profesor Ivana Novaković
DOI: https://doi.org/10.5937/mp73-35222
Ključne reči: LRRK2, rs34637584, Parkinsonova bolest, PCR u realnom vremenu

Sažetak


Uvod: Parkinsonova bolest (PB) pripada neurodegenerativnim oboljenjima, i sa prevalencijom od 1% do 2% kod osoba starijih od 65 godina i preko 4% kod starijih od 85 godina druga je po učestalosti u ovoj grupi bolesti. U osnovi PB se nalazi odumiranje dopaminergičkih neurona u CNS, pre svega u obasti bazalnih ganglija i substancie nigre. Gen LRRK2/PARK8 nalazi se na kratkom kraku hromozoma 12. U ovom genu opisane su različite varijante udružene sa PB, od kojih je najčešća mutacija c.6055G>A (p.Gly2019Ser), označena i kao rs34637584.

Istraživanje je sprovedeno sa ciljem da se utvrdi učestalost mutacije c.6055G>A tj. rs34637584 u genu LRRK2 kod grupe bolesnika sa PB iz Srbije.

Cilj ovog istraživanja je da se utvrdi učestalost mutacije c.6055G>A (rs34637584) u genu LRRK2 kod grupe bolesnika sa PB iz Srbije.

Materijal i metode: Ispitivanjem je obuhvaćena grupa od 127 bolesnika sa PB iz ustanove tercijarnog ranga u Srbiji, kao i odgovarajuća kontrolna grupa bez neuroloških bolesti. Molekularno genetička analiza je spovedena metodom PCR u realnom vremenu, upotrebom komercijalnog TaqMan eseja.

Rezultati: Mutacija c.6055G>A tj. rs34637584 varijanta je detektovana kod 1 od 127 ispitanika sa PB (0,7%), kod bolesnice bez prethodne familijarne istorije PB. Ova mutacija nije nađena u kontrolnoj grupi.

Zaključak: Dobijeni rezultati odgovaraju podacima iz literature za evropsku, posebno južnoevropsku populaciju. Testiranje mutacije LRRK2 c.6055G>A tj. rs34637584 treba da bude deo protokola ispitivanja PB.

Ključni pojmovi: LRRK2, rs34637584, Parkinsonova bolest, PCR u realnom vremenu

Reference


  1. Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic Parkinson’s disease. A clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry. 1992; 55(3):181-184.

  2. Bonifati V. LRRK2 low-penetrance mutations (Gly2019Ser) and risk alleles (Gly2385Arg)-Linking Familial and Sporadic Parkinson’s Disease. Neurochem Res. 2007; 32(10):1700-1708.

  3. Delamarre A, Meissner WG. Epidemiology, environmental risk factors and genetics of Parkinson’s disease. Presse Med. 2017; 46(2):175-181.

  4. Berg D, Schweitzer KJ, Leitner P, Zimprich A, Lichtner P, Belcredi P, et al. Type and frequency of mutations in the LRRK2 gene in familial and sporadic Parkinson’s disease. Brain. 2005; 128(12):3000-3011.

  5. Bialecka M, Hui S, Klodowska-Duda G, Opala G, Tan EK, Drozdzik M. Analysis of LRRK2 G2019S and I2020T mutations in Parkinson’s disease. Neurosci Lett. 2005; 390(1):1-3.

  6. Xiong Y, Dawson TM, Dawson VL. Models of LRRK2 associated Parkinson’s disease. Adv Neurobiol. 2017; 14:163–191.

  7. Kluss JH, Mamais A, Cookson MR. LRRK2 links genetic and sporadic Parkinson’s disease. Biochem Soc Trans. 2019; 47(2):651-661.

  8. Ramírez BM, Madero-Perez J, Rivero-Rios P, Martinez-Salvador M, Ordonez AJL, Fernandez B, et al. LRRK2 and Parkinson’s Disease: From Lack of Structure to Gain of Function. Curr Protein Pept Sci. 2017; 18(7):677-686.

  9. Tolosa E, Vila M, Klein C, Rascol O. LRRK2 in Parkinson disease: challenges of clinical trials. Nat Rev Neurol. 2020; 16(2):97-107.

  10. Chan SL, Tan E. Targeting LRRK2 in Parkinson’s disease: an update on recent developments. Expert Opin Ther Targets. 2017; 21(6):601-610.

  11. Biskup S, Moore DJ, Celsi F, Higashi S, West AB, Andrabi SA, et al. Localization of LRRK2 to membranous and vesicular structures in mammalian brain. Ann Neurol. 2006; 60(5): 557-569.

  12. Skibinski G, Nakamura K, Cookson MR, Finkbeiner S. Mutant LRRK2 toxicity in neurons depends on LRRK2 levels and synuclein but not kinase activity or inclusion bodies. J. Neurosci. 2014; 34(2): 418-433.

  13. Benson DL, Matikainen-Ankney BA, Hussein A, Huntley GW. Functional and behavioral consequences of Parkinson’s disease-associated LRRK2-G2019S mutation. Biochem Soc Trans. 2018; 46(6):1697-1705.

  14. Aasly JO, Vilarino-Guell C, Dachsel JC, Webber PJ, West AB, Haugarvoll K, et al. Novel pathogenic LRRK2 p.Asn1437His substitution in familial Parkinson’s disease. Mov Disord. 2010; 25(13):2156-2163.

  15. Bar-Shira A, Hutter CM, Giladi N, Zabetian CP, Orr-Urtreger A. Ashkenazi. Parkinson’s disease patients with the LRRK2 G2019S mutation share a common founder dating from the second to fifth centuries. Neurogenetics. 2009; 10(4):355-358.

  16. Ozelius LJ, Senthil G, Saunders-Pullman R, Ohmann E, Deligtisch A, Tagliati M, et al. LRRK2 G2019S as a cause of Parkinson's disease in Ashkenazi Jews. N Engl J Med. 2006; 354(4):424-425.

  17. Lesage S, Condroyer C, Lannuzel A, Lohmann E, Troiano A, Tison F, et al. Molecular analyses of the LRRK2 gene in European and North African autosomal dominant Parkinson’s disease. J Med Genet. 2009; 46(7): 458-464.

  18. Shojaee S, Sina F, Farboodi N, Fazlali Z, Ghazavi F, Ghorashi SA, et al. A clinic-based screening of mutations in exons 31, 34, 35, 41, and 48 of LRRK2 in Iranian Parkinson’s disease patients. Mov Disord. 2009; 24(7): 1023-1027.

  19. Healy DG, Falchi M, O’Sullivan SS, Bonifati V, Durr A, Bressman S, et al; International LRRK2 Consortium. Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson’s disease: a case-control study. Lancet Neurol 2008;7(7):583-590.

  20. Marder K, Wang Y, Alcalay RN, Mejia-Santana H, Tang MX, Lee A et al; LRRK2 Ashkenazi Jewish Consortium. Age-specific penetrance of LRRK2 G2019S in the Michael J. Fox Ashkenazi Jewish LRRK2 Consortium. Neurology 2015;85(1):89-95.

  21. Alcalay RN, Mejia-Santana H, Tang MX, Rosado L, Verbitsky M, Kisselev S et al. Motor phenotype of LRRK2 G2019S carriers in early-onset Parkinson disease. Arch Neurol. 2009;66(12):1517-1522.

  22. Kim CY, Alcalay RN. Genetic Forms of Parkinson’s Disease. Semin Neurol 2017;37(2):135-146.

Objavljeno
2022/10/19
Broj časopisa
Vol. 73 Br. 3 (2022): Medicinski podmladak
Rubrika
Originalni naučni članak