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Vol. 7, No. 1-3, 2010
Issue release date: April 2010
Section title: Imaging, Biomarkers, Genetics and Diagnostic Markers
Free Access
Neurodegenerative Dis 2010;7:170–174
(DOI:10.1159/000289231)

Common Variant in GRN Is a Genetic Risk Factor for Hippocampal Sclerosis in the Elderly

Dickson D.W. · Baker M. · Rademakers R.
Department of Neuroscience, Mayo Clinic, Jacksonville, Fla., USA
email Corresponding Author

Abstract

Background: Hippocampal sclerosis (HpScl) is common in elderly subjects with dementia, either alone or accompanied by other pathologic processes. It is also found in >70% of frontotemporal lobar degeneration with TDP-43 immunoreactive inclusions (FTLD-TDP). TDP-43 inclusions are detected in >20% of Alzheimer disease (AD) and >70% of HpScl cases. The most common cause of FTLD-TDP is mutation in the progranulin gene (GRN). Recently, a common genetic variant in the 3′ untranslated region (3′UTR) of GRN (rs5848; c.*78C>T) located in a microRNA binding site regulated progranulin expression, and the T-allele was increased in FTLD-TDP compared to controls. Objective: The goal of this study was to determine if the 3′UTR variant in GRN was associated with TDP-43 immunoreactivity in AD with and without HpScl. Methods: 644 cases of pathologically confirmed AD, including 57 with HpScl, were screened for TDP-43 immunoreactivity and were genotyped at the GRN 3′UTR single-nucleotide polymorphism rs5848 using previously published methods. Results: There was a trend (p = 0.06) for TDP-43 immunoreactivity, but a very significant (p = 0.005) association of HpScl with the variant, with 72% of AD with HpScl carrying a T-allele, compared to 51% of AD without HpScl carrying a T-allele. Conclusion: The results suggest that a genetic variant in GRN leading to decreased levels of progranulin may be a risk factor for HpScl in AD, while its role in TDP-43 immunoreactivity in AD remains less certain.

© 2010 S. Karger AG, Basel


  

Key Words

  • Alzheimer’s disease
  • Hippocampal sclerosis
  • Immunohistochemistry
  • Progranulin gene

References

  1. Dickson DW, Davies P, Bevona C, et al: Hippocampal sclerosis: a common pathological feature of dementia in very old (> or = 80 years of age) humans. Acta Neuropathol 1994;88:212–221.
  2. Zarow C, Sitzer TE, Chui HC: Understanding hippocampal sclerosis in the elderly: epidemiology, characterization, and diagnostic issues. Curr Neurol Neurosci Rep 2008;8:363–370.
  3. Hatanpaa KJ, Blass DM, Pletnikova O, et al: Most cases of dementia with hippocampal sclerosis may represent frontotemporal dementia. Neurology 2004;63:538–542.
  4. Blass DM, Hatanpaa KJ, Brandt J, et al: Dementia in hippocampal sclerosis resembles frontotemporal dementia more than Alzheimer disease. Neurology 2004;63:492–497.
  5. Josephs KA, Dickson DW: Hippocampal sclerosis in tau-negative frontotemporal lobar degeneration. Neurobiol Aging 2007;28:1718–1722.
  6. Petersen RC, Parisi JE, Dickson DW, et al: Neuropathologic features of amnestic mild cognitive impairment. Arch Neurol 2006;63:665–672.
  7. Sepe-Monti M, De Carolis A, Bomboi G, Castri P, Giubilei F: MRI evidence of bilateral hippocampal sclerosis in amnestic mild cognitive impairment. Eur J Neurol 2006;13:1031–1032.
  8. Kantarci K, Petersen RC, Przybelski SA, et al: Hippocampal volumes, proton magnetic resonance spectroscopy metabolites, and cerebrovascular disease in mild cognitive impairment subtypes. Arch Neurol 2008;65:1621–1628.
  9. Ala TA, Beh GO, Frey WH 2nd: Pure hippocampal sclerosis: a rare cause of dementia mimicking Alzheimer’s disease. Neurology 2000;54:843–848.
  10. Beach TG, Sue L, Scott S, et al: Hippocampal sclerosis dementia with tauopathy. Brain Pathol 2003;13:263–278.
  11. Togo T, Sahara N, Yen SH, et al: Argyrophilic grain disease is a sporadic 4-repeat tauopathy. J Neuropathol Exp Neurol 2002;61:547–556.
  12. Jicha GA, Petersen RC, Knopman DS, et al: Argyrophilic grain disease in demented subjects presenting initially with amnestic mild cognitive impairment. J Neuropathol Exp Neurol 2006;65:602–609.
  13. Obi T, Nishioka K, Ross OA, et al: Clinicopathologic study of a SNCA gene duplication patient with Parkinson disease and dementia. Neurology 2008;70:238–241.
  14. Farrer M, Kachergus J, Forno L, et al: Comparison of kindreds with parkinsonism and alpha-synuclein genomic multiplications. Ann Neurol 2004;55:174–179.
  15. Neumann M, Sampathu DM, Kwong LK, et al: Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 2006;314:130–133.
  16. Mackenzie IR, Neumann M, Bigio EH, et al: Nomenclature for neuropathologic subtypes of frontotemporal lobar degeneration: consensus recommendations. Acta Neuropathol 2009;117:15–18.
  17. Wang IF, Wu LS, Shen CK: TDP-43: an emerging new player in neurodegenerative diseases. Trends Mol Med 2008;14:479–485.
  18. Amador-Ortiz C, Lin WL, Ahmed Z, et al: TDP-43 immunoreactivity in hippocampal sclerosis and Alzheimer’s disease. Ann Neurol 2007;61:435–445.
  19. Hasegawa M, Arai T, Nonaka T, et al: Phosphorylated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Ann Neurol 2008;64:60–70.
  20. Probst A, Taylor KI, Tolnay M: Hippocampal sclerosis dementia: a reappraisal. Acta Neuropathol 2007;114:335–345.
  21. Baker M, Mackenzie IR, Pickering-Brown SM, et al: Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature 2006;442:916–919.
  22. Cruts M, Gijselinck I, van der Zee J, et al: Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature 2006;442:920–924.
  23. Gass J, Cannon A, Mackenzie IR, et al: Mutations in progranulin are a major cause of ubiquitin-positive frontotemporal lobar degeneration. Hum Mol Genet 2006;15:2988–3001.
  24. Josephs KA, Ahmed Z, Katsuse O, et al: Neuropathologic features of frontotemporal lobar degeneration with ubiquitin-positive inclusions with progranulin gene (PGRN) mutations. J Neuropathol Exp Neurol 2007;66:142–151.
  25. Mackenzie IR, Baker M, Pickering-Brown S, et al: The neuropathology of frontotemporal lobar degeneration caused by mutations in the progranulin gene. Brain 2006;129:3081–3090.
  26. Rademakers R, Eriksen JL, Baker M, et al: Common variation in the miR-659 binding-site of GRN is a major risk factor for TDP43-positive frontotemporal dementia. Hum Mol Genet 2008;17:3631–3642.
  27. Luis CA, Barker WW, Gajaraj K, et al: Sensitivity and specificity of three clinical criteria for dementia with Lewy bodies in an autopsy-verified sample. Int J Geriatr Psychiatry 1999;14:526–533.
  28. He Z, Bateman A: Progranulin (granulin-epithelin precursor, PC-cell-derived growth factor, acrogranin) mediates tissue repair and tumorigenesis. J Mol Med 2003;81:600–612.
  29. Bhandari V, Palfree RG, Bateman A: Isolation and sequence of the granulin precursor cDNA from human bone marrow reveals tandem cysteine-rich granulin domains. Proc Natl Acad Sci USA 1992;89:1715–1719.
  30. Bateman A, Belcourt D, Bennett H, Lazure C, Solomon S: Granulins, a novel class of peptide from leukocytes. Biochem Biophys Res Commun 1990;173:1161–1168.
  31. Ahmed Z, Mackenzie IR, Hutton ML, Dickson DW: Progranulin in frontotemporal lobar degeneration and neuroinflammation. J Neuroinflammation 2007;4:7.
  32. Polymeropoulos MH, Lavedan C, Leroy E, et al: Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 1997;276:2045–2047.
  33. Maraganore DM, de Andrade M, Elbaz A, et al: Collaborative analysis of alpha-synuclein gene promoter variability and Parkinson disease. JAMA 2006;296:661–670.
  34. He L, Hannon GJ: MicroRNAs: small RNAs with a big role in gene regulation. Nat Rev Genet 2004;5:522–531.
  35. Carthew RW, Sontheimer EJ: Origins and mechanisms of miRNAs and siRNAs. Cell 2009;136:642–655.
  36. Dickson DW: TDP-43 immunoreactivity in neurodegenerative disorders: disease versus mechanism specificity. Acta Neuropathol 2008;115:147–149.

  

Author Contacts

Dennis W. Dickson, MD
Department of Neuroscience, Mayo Clinic
4500 San Pablo Road
Jacksonville, FL 32224 (USA)
Tel. +1 904 953 7137, Fax +1 904 953 7117, E-Mail dickson.dennis@mayo.edu

  

Article Information

Published online: March 3, 2010
Number of Print Pages : 5
Number of Figures : 1, Number of Tables : 1, Number of References : 36

  

Publication Details

Neurodegenerative Diseases

Vol. 7, No. 1-3, Year 2010 (Cover Date: April 2010)

Journal Editor: Nitsch R.M. (Zürich), Hock C. (Zürich)
ISSN: 1660-2854 (Print), eISSN: 1660-2862 (Online)

For additional information: http://www.karger.com/NDD


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References

  1. Dickson DW, Davies P, Bevona C, et al: Hippocampal sclerosis: a common pathological feature of dementia in very old (> or = 80 years of age) humans. Acta Neuropathol 1994;88:212–221.
  2. Zarow C, Sitzer TE, Chui HC: Understanding hippocampal sclerosis in the elderly: epidemiology, characterization, and diagnostic issues. Curr Neurol Neurosci Rep 2008;8:363–370.
  3. Hatanpaa KJ, Blass DM, Pletnikova O, et al: Most cases of dementia with hippocampal sclerosis may represent frontotemporal dementia. Neurology 2004;63:538–542.
  4. Blass DM, Hatanpaa KJ, Brandt J, et al: Dementia in hippocampal sclerosis resembles frontotemporal dementia more than Alzheimer disease. Neurology 2004;63:492–497.
  5. Josephs KA, Dickson DW: Hippocampal sclerosis in tau-negative frontotemporal lobar degeneration. Neurobiol Aging 2007;28:1718–1722.
  6. Petersen RC, Parisi JE, Dickson DW, et al: Neuropathologic features of amnestic mild cognitive impairment. Arch Neurol 2006;63:665–672.
  7. Sepe-Monti M, De Carolis A, Bomboi G, Castri P, Giubilei F: MRI evidence of bilateral hippocampal sclerosis in amnestic mild cognitive impairment. Eur J Neurol 2006;13:1031–1032.
  8. Kantarci K, Petersen RC, Przybelski SA, et al: Hippocampal volumes, proton magnetic resonance spectroscopy metabolites, and cerebrovascular disease in mild cognitive impairment subtypes. Arch Neurol 2008;65:1621–1628.
  9. Ala TA, Beh GO, Frey WH 2nd: Pure hippocampal sclerosis: a rare cause of dementia mimicking Alzheimer’s disease. Neurology 2000;54:843–848.
  10. Beach TG, Sue L, Scott S, et al: Hippocampal sclerosis dementia with tauopathy. Brain Pathol 2003;13:263–278.
  11. Togo T, Sahara N, Yen SH, et al: Argyrophilic grain disease is a sporadic 4-repeat tauopathy. J Neuropathol Exp Neurol 2002;61:547–556.
  12. Jicha GA, Petersen RC, Knopman DS, et al: Argyrophilic grain disease in demented subjects presenting initially with amnestic mild cognitive impairment. J Neuropathol Exp Neurol 2006;65:602–609.
  13. Obi T, Nishioka K, Ross OA, et al: Clinicopathologic study of a SNCA gene duplication patient with Parkinson disease and dementia. Neurology 2008;70:238–241.
  14. Farrer M, Kachergus J, Forno L, et al: Comparison of kindreds with parkinsonism and alpha-synuclein genomic multiplications. Ann Neurol 2004;55:174–179.
  15. Neumann M, Sampathu DM, Kwong LK, et al: Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 2006;314:130–133.
  16. Mackenzie IR, Neumann M, Bigio EH, et al: Nomenclature for neuropathologic subtypes of frontotemporal lobar degeneration: consensus recommendations. Acta Neuropathol 2009;117:15–18.
  17. Wang IF, Wu LS, Shen CK: TDP-43: an emerging new player in neurodegenerative diseases. Trends Mol Med 2008;14:479–485.
  18. Amador-Ortiz C, Lin WL, Ahmed Z, et al: TDP-43 immunoreactivity in hippocampal sclerosis and Alzheimer’s disease. Ann Neurol 2007;61:435–445.
  19. Hasegawa M, Arai T, Nonaka T, et al: Phosphorylated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Ann Neurol 2008;64:60–70.
  20. Probst A, Taylor KI, Tolnay M: Hippocampal sclerosis dementia: a reappraisal. Acta Neuropathol 2007;114:335–345.
  21. Baker M, Mackenzie IR, Pickering-Brown SM, et al: Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature 2006;442:916–919.
  22. Cruts M, Gijselinck I, van der Zee J, et al: Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature 2006;442:920–924.
  23. Gass J, Cannon A, Mackenzie IR, et al: Mutations in progranulin are a major cause of ubiquitin-positive frontotemporal lobar degeneration. Hum Mol Genet 2006;15:2988–3001.
  24. Josephs KA, Ahmed Z, Katsuse O, et al: Neuropathologic features of frontotemporal lobar degeneration with ubiquitin-positive inclusions with progranulin gene (PGRN) mutations. J Neuropathol Exp Neurol 2007;66:142–151.
  25. Mackenzie IR, Baker M, Pickering-Brown S, et al: The neuropathology of frontotemporal lobar degeneration caused by mutations in the progranulin gene. Brain 2006;129:3081–3090.
  26. Rademakers R, Eriksen JL, Baker M, et al: Common variation in the miR-659 binding-site of GRN is a major risk factor for TDP43-positive frontotemporal dementia. Hum Mol Genet 2008;17:3631–3642.
  27. Luis CA, Barker WW, Gajaraj K, et al: Sensitivity and specificity of three clinical criteria for dementia with Lewy bodies in an autopsy-verified sample. Int J Geriatr Psychiatry 1999;14:526–533.
  28. He Z, Bateman A: Progranulin (granulin-epithelin precursor, PC-cell-derived growth factor, acrogranin) mediates tissue repair and tumorigenesis. J Mol Med 2003;81:600–612.
  29. Bhandari V, Palfree RG, Bateman A: Isolation and sequence of the granulin precursor cDNA from human bone marrow reveals tandem cysteine-rich granulin domains. Proc Natl Acad Sci USA 1992;89:1715–1719.
  30. Bateman A, Belcourt D, Bennett H, Lazure C, Solomon S: Granulins, a novel class of peptide from leukocytes. Biochem Biophys Res Commun 1990;173:1161–1168.
  31. Ahmed Z, Mackenzie IR, Hutton ML, Dickson DW: Progranulin in frontotemporal lobar degeneration and neuroinflammation. J Neuroinflammation 2007;4:7.
  32. Polymeropoulos MH, Lavedan C, Leroy E, et al: Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 1997;276:2045–2047.
  33. Maraganore DM, de Andrade M, Elbaz A, et al: Collaborative analysis of alpha-synuclein gene promoter variability and Parkinson disease. JAMA 2006;296:661–670.
  34. He L, Hannon GJ: MicroRNAs: small RNAs with a big role in gene regulation. Nat Rev Genet 2004;5:522–531.
  35. Carthew RW, Sontheimer EJ: Origins and mechanisms of miRNAs and siRNAs. Cell 2009;136:642–655.
  36. Dickson DW: TDP-43 immunoreactivity in neurodegenerative disorders: disease versus mechanism specificity. Acta Neuropathol 2008;115:147–149.