Neurogenetics

, Volume 8, Issue 2, pp 111–120

A novel gene derived from a segmental duplication shows perturbed expression in Alzheimer’s disease

  • Dimitrios Avramopoulos
  • Ruihua Wang
  • David Valle
  • M. Daniele Fallin
  • Susan S. Bassett
Original Article

Abstract

Alzheimer’s disease (AD) is a disabling neurodegenerative disorder with onset commonly in late life. Three genes have been identified causing earlier onset AD, and a fourth has been shown to be a risk factor for late onset AD (LOAD), while many more yet unrecognized genes are thought to contribute to susceptibility. Many studies have reported linkage to LOAD on human chromosome 10, where we have identified a parent of origin effect [Bassett SS, Avramopoulos D, Perry RT, Wiener H, Watson B Jr, Go RC, Fallin MD. Am J Med Genet B Neuropsychiatr Genet 141:537–540, (2006), Bassett SS, Avramopoulos D, Fallin D. Am J Med Genet 114:679–686, (2002)]. In this paper, we report on a gene in this region that shows reduced expression with increasing age, reduced expression in females across ages, and further reduction in LOAD patients. In concordance with the observed parent of origin effect on the linkage, this reduction is more pronounced in patients with an affected mother. We discovered this gene while studying the alkaline ceramidase gene (ASAH2); it is a partial paralog of ASAH2, and we call it ASAH2L. It is the result of a partial duplication of ASAH2 on chromosome 10q11.23, just downstream from the sequence with promoter activity. ASAH2L has a polymorphic start codon with a single nucleotide change of the original ASAH2 sequence plus other putative translation start sites that might produce novel proteins. It is expressed in all the tissues we tested including the brain and is an interesting example of the generation of a new gene. Comparison of primate and other mammal genomes suggests that ASAH2L is human specific. Further research would be necessary to determine the function of the ASAH2L transcript and explore any possible involvement in neurodegeneration.

Keywords

Brain Alzheimer disease Gene Gene duplication Gene expression 

References

  1. 1.
    Bassett SS, Avramopoulos D, Perry RT, Wiener H, Watson B Jr, Go RC, Fallin MD (2006) Further evidence of a maternal parent-of-origin effect on chromosome 10 in late-onset Alzheimer’s disease. Am J Med Genet B Neuropsychiatr Genet 141:537–540PubMedGoogle Scholar
  2. 2.
    Bassett SS, Avramopoulos D, Fallin D (2002) Evidence for parent of origin effect in late-onset Alzheimer disease. Am J Med Genet 114:679–686PubMedCrossRefGoogle Scholar
  3. 3.
    Miech RA, Breitner JC, Zandi PP, Khachaturian AS, Anthony JC, Mayer L (2002) Incidence of AD may decline in the early 90s for men, later for women: the cache county study. Neurology 58:209–218PubMedGoogle Scholar
  4. 4.
    Devi G, Ottman R, Tang MX, Marder K, Stern Y, Mayeux R (2000) Familial aggregation of Alzheimer disease among whites, African Americans, and Caribbean Hispanics in northern Manhattan. Arch Neurol 57:72–77PubMedCrossRefGoogle Scholar
  5. 5.
    Bergem AL, Engedal K, Kringlen E (1997) The role of heredity in late-onset Alzheimer disease and vascular dementia. A twin study. Arch Gen Psychiatry 54:264–270PubMedGoogle Scholar
  6. 6.
    Gatz M, Pedersen NL, Berg S, Johansson B, Johansson K, Mortimer JA, Posner SF, Viitanen M, Winblad B, Ahlbom A (1997) Heritability for Alzheimer's disease: the study of dementia in Swedish twins. J Gerontol Ser A Biol Sci Med Sci 52:M117–M125Google Scholar
  7. 7.
    Goate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, Fidani L, Giuffra L, Haynes A, Irving N, James L et al (1991) Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature 349:704–706PubMedCrossRefGoogle Scholar
  8. 8.
    Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, Chi H, Lin C, Li G, Holman K et al (1995) Cloning of a gene bearing missense mutations in early-onset familial Alzheimer’s disease. Nature 375:754–760PubMedCrossRefGoogle Scholar
  9. 9.
    Levy-Lahad E, Wijsman EM, Nemens E, Anderson L, Goddard KA, Weber JL, Bird TD, Schellenberg GD (1995) A familial Alzheimer’s disease locus on chromosome 1. Science 269:970–973PubMedCrossRefGoogle Scholar
  10. 10.
    Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M, Enghild J, Salvesen GS, Roses AD (1993) Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci USA 90:1977–1981PubMedCrossRefGoogle Scholar
  11. 11.
    Brookes AJ, Prince JA (2005) Genetic association analysis: lessons from the study of Alzheimers disease. Mutat Res 573:152–159PubMedGoogle Scholar
  12. 12.
    Kamboh MI (2004) Molecular genetics of late-onset Alzheimer’s disease. Ann Hum Genet 68:381–404PubMedCrossRefGoogle Scholar
  13. 13.
    Lendon C, Craddock N (2001) Susceptibility gene(s) for Alzheimer’s disease on chromosome 10. Trends Neurosci 24:557–559PubMedCrossRefGoogle Scholar
  14. 14.
    Walsh JB (1995) How often do duplicated genes evolve new functions? Genetics 139:421–428PubMedGoogle Scholar
  15. 15.
    Long M, Langley CH (1993) Natural selection and the origin of jingwei, a chimeric processed functional gene in Drosophila. Science 260:91–95PubMedCrossRefGoogle Scholar
  16. 16.
    Samonte RV, Eichler EE (2002) Segmental duplications and the evolution of the primate genome. Nat Rev Genet 3:65–72PubMedCrossRefGoogle Scholar
  17. 17.
    Lupski JR, Stankiewicz P (2005) Genomic disorders: molecular mechanisms for rearrangements and conveyed phenotypes. PLoS Genet 1:e49PubMedCrossRefGoogle Scholar
  18. 18.
    Sharp AJ, Locke DP, McGrath SD, Cheng Z, Bailey JA, Vallente RU, Pertz LM, Clark RA, Schwartz S, Segraves R et al (2005) Segmental duplications and copy-number variation in the human genome. Am J Hum Genet 77:78–88PubMedCrossRefGoogle Scholar
  19. 19.
    Blacker D, Bertram L, Saunders AJ, Moscarillo TJ, Albert MS, Wiener H, Perry RT, Collins JS, Harrell LE, Go RC et al (2003) Results of a high-resolution genome screen of 437 Alzheimer’s disease families. Hum Mol Genet 12:23–32PubMedCrossRefGoogle Scholar
  20. 20.
    Busatto GF, Garrido GE, Almeida OP, Castro CC, Camargo CH, Cid CG, Buchpiguel CA, Furuie S, Bottino CM (2003) A voxel-based morphometry study of temporal lobe gray matter reductions in Alzheimer’s disease. Neurobiol Aging 24:221–231PubMedCrossRefGoogle Scholar
  21. 21.
    Bajic VB, Tan SL, Chong A, Tang S, Strom A, Gustafsson JA, Lin CY, Liu ET (2003) Dragon ERE Finder version 2: a tool for accurate detection and analysis of estrogen response elements in vertebrate genomes. Nucleic Acids Res 31:3605–3607PubMedCrossRefGoogle Scholar
  22. 22.
    Kozak M (1984) Compilation and analysis of sequences upstream from the translational start site in eukaryotic mRNAs. Nucleic Acids Res 12:857–872PubMedCrossRefGoogle Scholar
  23. 23.
    Kozak M (1986) Point mutations define a sequence flanking the AUG initiator codon that modulates translation by eukaryotic ribosomes. Cell 44:283–292PubMedCrossRefGoogle Scholar
  24. 24.
    Altschul SF, Gish W, Miller W, Myers EW, Lipman DJ (1990) Basic local alignment search tool. J Mol Biol 215:403–410PubMedGoogle Scholar
  25. 25.
    El Bawab S, Roddy P, Qian T, Bielawska A, Lemasters JJ, Hannun YA (2000) Molecular cloning and characterization of a human mitochondrial ceramidase. J Biol Chem 275:21508–21513PubMedCrossRefGoogle Scholar
  26. 26.
    Choi MS, Anderson MA, Zhang Z, Zimonjic DB, Popescu N, Mukherjee AB (2003) Neutral ceramidase gene: role in regulating ceramide-induced apoptosis. Gene 315:113–122PubMedCrossRefGoogle Scholar
  27. 27.
    Kono M, Dreier JL, Ellis JM, Allende ML, Kalkofen DN, Sanders KM, Bielawski J, Bielawska A, Hannun YA, Proia RL (2006) Neutral ceramidase encoded by the asah2 gene is essential for the intestinal degradation of sphingolipids. J Biol Chem 281:7324–7331PubMedCrossRefGoogle Scholar
  28. 28.
    Yoshimura Y, Tani M, Okino N, Iida H, Ito M (2004) Molecular cloning and functional analysis of zebrafish neutral ceramidase. J Biol Chem 279:44012–44022PubMedCrossRefGoogle Scholar
  29. 29.
    El Bawab S, Bielawska A, Hannun YA (1999) Purification and characterization of a membrane-bound nonlysosomal ceramidase from rat brain. J Biol Chem 274:27948–27955PubMedCrossRefGoogle Scholar
  30. 30.
    Tani M, Okino N, Mori K, Tanigawa T, Izu H, Ito M (2000) Molecular cloning of the full-length cDNA encoding mouse neutral ceramidase. A novel but highly conserved gene family of neutral/alkaline ceramidases. J Biol Chem 275:11229–11234PubMedCrossRefGoogle Scholar
  31. 31.
    Hwang YH, Tani M, Nakagawa T, Okino N, Ito M (2005) Subcellular localization of human neutral ceramidase expressed in HEK293 cells. Biochem Biophys Res Commun 331:37–42PubMedCrossRefGoogle Scholar
  32. 32.
    Green DR, Reed JC (1998) Mitochondria and apoptosis. Science 281:1309–1312PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Dimitrios Avramopoulos
    • 1
    • 2
  • Ruihua Wang
    • 1
  • David Valle
    • 2
  • M. Daniele Fallin
    • 3
    • 4
  • Susan S. Bassett
    • 1
  1. 1.Department of Psychiatry, School of MedicineJohns Hopkins UniversityBaltimoreUSA
  2. 2.McKusick–Nathans Institute of Genetic Medicine, School of MedicineJohns Hopkins UniversityBaltimoreUSA
  3. 3.Department of EpidemiologyJohns Hopkins Bloomberg School of Public HealthBaltimoreUSA
  4. 4.Department of BiostatisticsJohns Hopkins Bloomberg School of Public HealthBaltimoreUSA

Personalised recommendations