TMEM106B is a genetic modifier of frontotemporal lobar degeneration with C9orf72 hexanucleotide repeat expansions

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• 作者：Michael D. Gallagher (1) (2)
  Eunran Suh (3)
  Murray Grossman (2)
  Lauren Elman (2)
  Leo McCluskey (2)
  John C. Van Swieten (4) (5)
  Safa Al-Sarraj (6)
  Manuela Neumann (7) (8)
  Ellen Gelpi (9)
  Bernardino Ghetti (10)
  Jonathan D. Rohrer (11)
  Glenda Halliday (12) (13)
  Christine Van Broeckhoven (14)
  Danielle Seilhean (15)
  Pamela J. Shaw (16)
  Matthew P. Frosch (17)
  Irina Alafuzoff (18)
  Anna Antonell (19)
  Nenad Bogdanovic (20)
  William Brooks (12) (13)
  Nigel J. Cairns (21)
  Johnathan Cooper-Knock (16)
  Carl Cotman (22)
  Patrick Cras (23) (24)
  Marc Cruts (23) (25)
  Peter P. De Deyn (23) (26)
  Charles DeCarli (27)
  Carol Dobson-Stone (12) (13)
  Sebastiaan Engelborghs (23) (26)
  Nick Fox (28)
  Douglas Galasko (29)
  Marla Gearing (30)
  Ilse Gijselinck (23) (25)
  Jordan Grafman (31)
  P?ivi Hartikainen (32)
  Kimmo J. Hatanpaa (33)
  J. Robin Highley (16)
  John Hodges (12) (13)
  Christine Hulette (34)
  Paul G. Ince (16)
  Lee-Way Jin (27)
  Janine Kirby (16)
  Julia Kofler (35)
  Jillian Kril (36)
  John B. J. Kwok (12) (13)
  Allan Levey (30)
  Andrew Lieberman (37)
  Albert Llado (19)
  Jean-Jacques Martin (23)
  Eliezer Masliah (29)
  Christopher J. McDermott (16)
  Ann McKee (38)
  Catriona McLean (39)
  Simon Mead (40)
  Carol A. Miller (41)
  Josh Miller (27)
  David G. Munoz (42)
  Jill Murrell (43)
  Henry Paulson (37)
  Olivier Piguet (12) (13)
  Martin Rossor (28)
  Raquel Sanchez-Valle (19)
  Mary Sano (44)
  Julie Schneider (45)
  Lisa C. Silbert (46)
  Salvatore Spina (43)
  Julie van der Zee (23) (25)
  Tim Van Langenhove (23) (24) (25)
  Jason Warren (28)
  Stephen B. Wharton (16)
  Charles L. White III (33)
  Randall L. Woltjer (46)
  John Q. Trojanowski (3)
  Virginia M. Y. Lee (3)
  Vivianna Van Deerlin (3)
  Alice S. Chen-Plotkin (2)
  
• 关键词：TMEM106B ; C9orf72 ; Frontotemporal dementia ; Frontotemporal lobar degeneration ; Amyotrophic lateral sclerosis ; Genetic modifier
• 刊名：Acta Neuropathologica
• 出版年：2014
• 出版时间：March 2014
• 年：2014
• 卷：127
• 期：3
• 页码：407-418
• 全文大小：686 KB
• 作者单位：Michael D. Gallagher (1) (2)
  Eunran Suh (3)
  Murray Grossman (2)
  Lauren Elman (2)
  Leo McCluskey (2)
  John C. Van Swieten (4) (5)
  Safa Al-Sarraj (6)
  Manuela Neumann (7) (8)
  Ellen Gelpi (9)
  Bernardino Ghetti (10)
  Jonathan D. Rohrer (11)
  Glenda Halliday (12) (13)
  Christine Van Broeckhoven (14)
  Danielle Seilhean (15)
  Pamela J. Shaw (16)
  Matthew P. Frosch (17)
  Irina Alafuzoff (18)
  Anna Antonell (19)
  Nenad Bogdanovic (20)
  William Brooks (12) (13)
  Nigel J. Cairns (21)
  Johnathan Cooper-Knock (16)
  Carl Cotman (22)
  Patrick Cras (23) (24)
  Marc Cruts (23) (25)
  Peter P. De Deyn (23) (26)
  Charles DeCarli (27)
  Carol Dobson-Stone (12) (13)
  Sebastiaan Engelborghs (23) (26)
  Nick Fox (28)
  Douglas Galasko (29)
  Marla Gearing (30)
  Ilse Gijselinck (23) (25)
  Jordan Grafman (31)
  P?ivi Hartikainen (32)
  Kimmo J. Hatanpaa (33)
  J. Robin Highley (16)
  John Hodges (12) (13)
  Christine Hulette (34)
  Paul G. Ince (16)
  Lee-Way Jin (27)
  Janine Kirby (16)
  Julia Kofler (35)
  Jillian Kril (36)
  John B. J. Kwok (12) (13)
  Allan Levey (30)
  Andrew Lieberman (37)
  Albert Llado (19)
  Jean-Jacques Martin (23)
  Eliezer Masliah (29)
  Christopher J. McDermott (16)
  Ann McKee (38)
  Catriona McLean (39)
  Simon Mead (40)
  Carol A. Miller (41)
  Josh Miller (27)
  David G. Munoz (42)
  Jill Murrell (43)
  Henry Paulson (37)
  Olivier Piguet (12) (13)
  Martin Rossor (28)
  Raquel Sanchez-Valle (19)
  Mary Sano (44)
  Julie Schneider (45)
  Lisa C. Silbert (46)
  Salvatore Spina (43)
  Julie van der Zee (23) (25)
  Tim Van Langenhove (23) (24) (25)
  Jason Warren (28)
  Stephen B. Wharton (16)
  Charles L. White III (33)
  Randall L. Woltjer (46)
  John Q. Trojanowski (3)
  Virginia M. Y. Lee (3)
  Vivianna Van Deerlin (3)
  Alice S. Chen-Plotkin (2)
  
  1. Cell and Molecular Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
  2. Department of Neurology, Perelman School of Medicine, University of Pennsylvania, 3 W Gates, 3400 Spruce St, Philadelphia, PA, 19104, USA
  3. Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
  4. Erasmus Medical Centre, s’Gravendijkwal 230, Rotterdam, The Netherlands
  5. Alzheimercenter Vumc, Boelelaan, 1118, Amsterdam, The Netherlands
  6. King’s College Hospital, London, UK
  7. University of Tübingen, Calwerstr. 3, 72072, Tübingen, Germany
  8. German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
  9. Neurological Tissue Bank of the Biobank-Hospital Clinic-Insitut d’Investigacions Biomèdiques August Pi i Sunyer, Facultad de Medicina, c/Casanova 143, planta 0, ala sur., 08036, Barcelona, Spain
  10. Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
  11. Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK
  12. Neuroscience Research Australia, Barker St, Randwick, NSW, 2031, Australia
  13. Faculty of Medicine, University of New South Wales, Sydney, Australia
  14. Neurodegenerative Brain Disease Group, Department of Molecular Genetics, VIB, Universiteitsplein 1, 2610, Antwerp, Belgium
  15. University Pierre et Marie Curie (UPMC)-Sorbonne University, Paris, France
  16. University of Sheffield, SITraN, 385a Glossop Road, Sheffield, S10 2HQ, UK
  17. Massachusetts Alzheimer’s Disease Research Center, Harvard Medical School, Boston, MA, USA
  18. Uppsala University, Uppsala, Sweden
  19. Alzheimer and Cognitive Disorders Unit, Neurology Service, Hospital Clinic de Barcelona, Spain, c/Villarroel 170, 08036, Barcelona, Spain
  20. Karolinska Institutet, NVS, NOVUM plan 5, Solna, Sweden
  21. Washington University School of Medicine, St. Louis, MO, 63110, USA
  22. University of California, Irvine, Irvine, USA
  23. Institute Born-Bunge, University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Belgium
  24. Department of Neurology, Antwerp University Hospital, Wilrijkstraat 10, 2650, Edegem, Belgium
  25. Department of Molecular Genetics, VIB, Universiteitsplein 1, 2610, Antwerp, Belgium
  26. Department of Neurology, Hospital Network Antwerp (ZNA) Middelheim, Lindendreef 1, 2020, Antwerp, Belgium
  27. University of California, Davis, USA
  28. Department of Neurodegenerative Disease, Dementia Research Centre, University College London Institute of Neurology, Queen Square, London, UK
  29. University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0948, USA
  30. Emory University, Atlanta, USA
  31. Northwestern University, Chicago, USA
  32. Kuopio University Hospital, Kuopio, Finland
  33. University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75390-9073, USA
  34. Duke University Medical Center, Durham, NC, USA
  35. Department of Pathology, University of Pittsburgh, 200 Lothrop Street, PUH South Tower Rm M8737, Pittsburgh, PA, 15213, USA
  36. Department of Pathology, Sydney Medical School, The University of Sydney, Sydney, NSW, 2006, Australia
  37. University of Michigan, Ann Arbor, USA
  38. Boston University, Boston, USA
  39. Australian Brain Bank Network, The Florey Institute of Neuroscience and Mental Health, Melbourne Brain Centre, Parkville, Australia
  40. MRC Prion Unit, Department of Neurodegenerative Disease, University College London Institute of Neurology, Queen Square, London, UK
  41. Keck School of Medicine of University of Southern California, 2011 Zonal Ave., MCA-341, Los Angeles, USA
  42. University of Toronto, Toronto, ON, USA
  43. Indiana University, Bloomington, USA
  44. Mount Sinai School of Medicine, New York, USA
  45. Rush University Medical Center, Chicago, USA
  46. Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97230, USA
  
• ISSN：1432-0533

文摘

Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9orf72) have recently been linked to frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis, and may be the most common genetic cause of both neurodegenerative diseases. Genetic variants at TMEM106B influence risk for the most common neuropathological subtype of FTLD, characterized by inclusions of TAR DNA-binding protein of 43?kDa (FTLD-TDP). Previous reports have shown that TMEM106B is a genetic modifier of FTLD-TDP caused by progranulin (GRN) mutations, with the major (risk) allele of rs1990622 associating with earlier age at onset of disease. Here, we report that rs1990622 genotype affects age at death in a single-site discovery cohort of FTLD patients with C9orf72 expansions (n?=?14), with the major allele correlated with later age at death (p?=?0.024). We replicate this modifier effect in a 30-site international neuropathological cohort of FTLD-TDP patients with C9orf72 expansions (n?=?75), again finding that the major allele associates with later age at death (p?=?0.016), as well as later age at onset (p?=?0.019). In contrast, TMEM106B genotype does not affect age at onset or death in 241 FTLD-TDP cases negative for GRN mutations or C9orf72 expansions. Thus, TMEM106B is a genetic modifier of FTLD with C9orf72 expansions. Intriguingly, the genotype that confers increased risk for developing FTLD-TDP (major, or T, allele of rs1990622) is associated with later age at onset and death in C9orf72 expansion carriers, providing an example of sign epistasis in human neurodegenerative disease.