J Korean Med Sci.  2008 Apr;23(2):213-217. 10.3346/jkms.2008.23.2.213.

Identification of PSEN1 and APP Gene Mutations in Korean Patients with Early-Onset Alzheimer's Disease

• Park HK
• Na DL
• Lee JH
• Kim JW
• Ki CS

• KMID: 1713451
• DOI: http://doi.org/10.3346/jkms.2008.23.2.213

Abstract

Although mutations in three genes, amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2), have been identified as genetic causes of earlyonset Alzheimer s disease (EOAD), there has been a single report on a PSEN1 mutation in Koreans. In the present study, we performed a genetic analysis of six Korean patients with EOAD. Direct sequencing analysis of the APP, PSEN1 and PSEN2 genes revealed two different mutations of the PSEN1 gene (G206S and M233T) and one mutation of the APP gene (V715M) in three patients with age-atonset of 34, 35, and 42 yr, respectively. In addition, two patients with age-at-onset of 55 and 62 yr, respectively, were homozygous for APOE epsilon 4 allele. One woman had no genetic alterations. These findings suggest that PSEN1 and APP gene mutations may not be uncommon in Korean patients with EOAD and that genetic analysis should be provided to EOAD patients not only for the identification of their genetic causes but also for the appropriate genetic counseling.

Keyword

Amyloid beta-Protein Precursor; Alzheimer Disease; Presenilin-1; Presenilin-2; Mutation

MeSH Terms

Adult
Alleles
Alzheimer Disease/*genetics
Amyloid/*genetics
Apolipoproteins E/*genetics
Female
Humans
Korea
Male
Middle Aged
Models, Genetic
*Mutation
Pedigree
Presenilin-1/*genetics
Sequence Analysis, DNA

Figure

• 

  Fig. 1 Pedigrees of Korean patients with EOAD. Numbers below symbols are age-at-onset and age-at-deceased, respectively. Circle, female; square, male; filled symbol, affected; open symbol, not affected; open symbol with a question mark, affected status not known; question mark, age-at-onset not known; horizontal bar, alive.

• 

  Fig. 2 Comparison of brain FDG-PET images from a cognitively normal control and four patients with EOAD. FDG-PET images (B-E) show variable degrees of hypometabolism in temporoparietal and frontal cortex, which are typical for Alzheimer's disease. (A) a 55-yr-old healthy Korean with a K-MMSE score of 30, (B) patient 2; 3 yr after the first symptom with a K-MMSE score of 22, (C) patient 3; 4 yr after the first symptom with a K-MMSE score of 4, (D) patient 5; 3 yr after the first symptom with a K-MMSE score of 18; (E) patient 6; 3 yr after the first symptom with a K-MMSE score of 11.

Reference

1. Cruts M, van Duijn CM, Backhovens H, Van den Broeck M, Wehnert A, Serneels S, Sherrington R, Hutton M, Hardy J, St George-Hyslop PH, Hofman A, Van Broeckhoven C. Estimation of the genetic contribution of presenilin-1 and -2 mutations in a population-based study of presenile Alzheimer disease. Hum Mol Genet. 1998. 7:43–51.

2. Finckh U, Muller-Thomsen T, Mann U, Eggers C, Marksteiner J, Meins W, Binetti G, Alberici A, Hock C, Nitsch RM, Gal A. High prevalence of pathogenic mutations in patients with early-onset dementia detected by sequence analyses of four different genes. Am J Hum Genet. 2000. 66:110–117.

3. Goate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, Fidani L, Giuffra L, Haynes A, Irving N, James L, Mant R, Newton P, Rooke K, Roques P, Talbot C, Pericak-Vance M, Roses A, Williamson R, Rossor M, Owen M, Hardy J. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature. 1991. 349:704–706.

4. Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, Chi H, Lin C, Li G, Holman K, Tsuda T, Mar L, Foncin JF, Bruni AC, Montesi MP, Sorbi S, Rainero I, Pinessi L, Nee L, Chumakov I, Pollen D, Brookes A, Sanseau P, Polinsky RJ, Wasco W, Da Silva HAR, Haines JL, Pericak-Vance MA, Tanzi RE, Roses AD, Fraser PE, Rommens JM, St George-Hyslop PH. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature. 1995. 375:754–760.

5. Rogaev EI, Sherrington R, Rogaeva EA, Levesque G, Ikeda M, Liang Y, Chi H, Lin C, Holman K, Tsuda T, Mar L, Sorbi S, Nacmias B, Placentini S, Amaducci L, Chumakov I, Cohen D, Lannfelt L, Fraser PE, Rommens JM, St George-Hyslop PH. Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene. Nature. 1995. 376:775–778.

6. Levy-Lahad E, Wasco W, Poorkaj P, Romano DM, Oshima J, Pettingell WH, Yu CE, Jondro PD, Schmidt SD, Wang K, Crowley AC, Fu YH, Guenette SY, Galas D, Nemens E, Wijsman EM, Bird TD, Schellenberg GD, Tanzi RE. Candidate gene for the chromosome 1 familial Alzheimer's disease locus. Science. 1995. 269:973–977.

7. Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science. 1993. 261:921–923.

8. Saunders AM, Strittmatter WJ, Schmechel D, George-Hyslop PH, Pericak-Vance MA, Joo SH, Rosi BL, Gusella JF, Crapper-MacLachlan DR, Alberts MJ, Hulette C, Crain B, Goldgaber D, Roses AD. Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer's disease. Neurology. 1993. 43:1467–1472.

9. van Duijn CM, de Knijff P, Cruts M, Wehnert A, Havekes LM, Hofman A, Van Broeckhoven C. Apolipoprotein E4 allele in a population-based study of early-onset Alzheimer's disease. Nat Genet. 1994. 7:74–78.

10. Campion D, Dumanchin C, Hannequin D, Dubois B, Belliard S, Puel M, Thomas-Anterion C, Michon A, Martin C, Charbonnier F, Raux G, Camuzat A, Penet C, Mesnage V, Martinez M, Clerget-Darpoux F, Brice A, Frebourg T. Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. Am J Hum Genet. 1999. 65:664–670.

11. Lao JI, Beyer K, Fernandez-Novoa L, Cacabelos R. A novel mutation in the predicted TM2 domain of the presenilin 2 gene in a Spanish patient with late-onset Alzheimer's disease. Neurogenetics. 1998. 1:293–296.

12. Esler WP, Wolfe MS. A portrait of Alzheimer secretases--new features and familiar faces. Science. 2001. 293:1449–1454.

13. Scheuner D, Eckman C, Jensen M, Song X, Citron M, Suzuki N, Bird TD, Hardy J, Hutton M, Kukull W, Larson E, Levy-Lahad E, Viitanen M, Peskind E, Poorkaj P, Schellenberg G, Tanzi R, Wasco W, Lannfelt L, Selkoe D, Younkin S. Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease. Nat Med. 1996. 2:864–870.

14. Ancolio K, Dumanchin C, Barelli H, Warter JM, Brice A, Campion D, Frebourg T, Checler F. Unusual phenotypic alteration of beta amyloid precursor protein (betaAPP) maturation by a new Val-715 --> Met betaAPP-770 mutation responsible for probable early-onset Alzheimer's disease. Proc Natl Acad Sci USA. 1999. 96:4119–4124.

15. Hong KS, Kim SP, Na DL, Kim JG, Suh YL, Kim SE, Kim JW. Clinical and genetic analysis of a pedigree of a thirty-six-year-old familial Alzheimer's disease patient. Biol Psychiatry. 1997. 42:1172–1176.

16. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer's disease: report of the NINCDSADRDA Work Group under the auspices of department of health and human services task force on Alzheimer's disease. Neurology. 1984. 34:939–944.

17. Raux G, Guyant-Marechal L, Martin C, Bou J, Penet C, Brice A, Hannequin D, Frebourg T, Campion D. Molecular diagnosis of autosomal dominant early onset Alzheimer's disease: an update. J Med Genet. 2005. 42:793–795.

18. Rogaeva EA, Fafel KC, Song YQ, Medeiros H, Sato C, Liang Y, Richard E, Rogaev EI, Frommelt P, Sadovnick AD, Meschino W, Rockwood K, Boss MA, Mayeux R, St George-Hyslop P. Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations. Neurology. 2001. 57:621–625.

19. Kwok JB, Taddei K, Hallupp M, Fisher C, Brooks WS, Broe GA, Hardy J, Fulham MJ, Nicholson GA, Stell R, St George Hyslop PH, Fraser PE, Kakulas B, Clarnette R, Relkin N, Gandy SE, Schofield PR, Martins RN. Two novel (M233T and R278T) presenilin-1 mutations in early-onset Alzheimer's disease pedigrees and preliminary evidence for association of presenilin-1 mutations with a novel phenotype. Neuroreport. 1997. 8:1537–1542.

20. Kang SY, Lee WI. Apolipoprotein E polymorphism in ischemic stroke patients with different pathogenetic origins. Korean J Lab Med. 2006. 26:210–216.

21. Kim JH, Lim HS, Kwon OH. Polymorphisms of apolipoprotein B and apolipoprotein E in hypobetalipoproteinemic Korean. Korean J Lab Med. 2002. 22:388–394.

22. Ki CS, Na DL, Kim HJ, Kim JW. Alpha-1 antichymotrypsin and alpha-2 macroglobulin gene polymorphisms are not associated with Korean late-onset Alzheimer's disease. Neurosci Lett. 2001. 302:69–72.

23. Shin MH, Kim HN, Cui LH, Kweon SS, Park KS, Heo H, Nam HS, Jeong SK, Chung EK, Choi JS. The effect of apolipoprotein E polymorphism on lipid levels in Korean adults. J Korean Med Sci. 2005. 20:361–366.

24. Janssen JC, Beck JA, Campbell TA, Dickinson A, Fox NC, Harvey RJ, Houlden H, Rossor MN, Collinge J. Early onset familial Alzheimer's disease: Mutation frequency in 31 families. Neurology. 2003. 60:235–239.