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Acta Neuropathologica

, Volume 127, Issue 3, pp 397–406 | Cite as

TMEM106B protects C9ORF72 expansion carriers against frontotemporal dementia

  • Marka van Blitterswijk
  • Bianca Mullen
  • Alexandra M. Nicholson
  • Kevin F. Bieniek
  • Michael G. Heckman
  • Matthew C. Baker
  • Mariely DeJesus-Hernandez
  • NiCole A. Finch
  • Patricia H. Brown
  • Melissa E. Murray
  • Ging-Yuek R. Hsiung
  • Heather Stewart
  • Anna M. Karydas
  • Elizabeth Finger
  • Andrew Kertesz
  • Eileen H. Bigio
  • Sandra Weintraub
  • Marsel Mesulam
  • Kimmo J. Hatanpaa
  • Charles L. White III
  • Michael J. Strong
  • Thomas G. Beach
  • Zbigniew K. Wszolek
  • Carol Lippa
  • Richard Caselli
  • Leonard Petrucelli
  • Keith A. Josephs
  • Joseph E. Parisi
  • David S. Knopman
  • Ronald C. Petersen
  • Ian R. Mackenzie
  • William W. Seeley
  • Lea T. Grinberg
  • Bruce L. Miller
  • Kevin B. Boylan
  • Neill R. Graff-Radford
  • Bradley F. Boeve
  • Dennis W. Dickson
  • Rosa RademakersEmail author
Original Paper

Abstract

Variants in transmembrane protein 106 B (TMEM106B) modify the disease penetrance of frontotemporal dementia (FTD) in carriers of progranulin (GRN) mutations. We investigated whether TMEM106B is also a genetic modifier of disease in carriers of chromosome 9 open reading frame 72 (C9ORF72) expansions. We assessed the genotype of 325 C9ORF72 expansion carriers (cohort 1), 586 FTD patients lacking C9ORF72 expansions [with or without motor neuron disease (MND); cohort 2], and a total of 1,302 controls for TMEM106B variants (rs3173615 and rs1990622) using MassArray iPLEX and Taqman genotyping assays. For our primary analysis, we focused on functional variant rs3173615, and employed a recessive genotypic model. In cohort 1, patients with C9ORF72 expansions showed a significantly reduced frequency of carriers homozygous for the minor allele as compared to controls [11.9 vs. 19.1 %, odds ratio (OR) 0.57, p = 0.014; same direction as carriers of GRN mutations]. The strongest evidence was provided by FTD patients (OR 0.33, p = 0.009) followed by FTD/MND patients (OR 0.38, p = 0.017), whereas no significant difference was observed in MND patients (OR 0.85, p = 0.55). In cohort 2, the frequency of carriers homozygous for the minor allele was not significantly reduced in patients as compared to controls (OR 0.77, p = 0.079); however, a significant reduction was observed when focusing on those patients with frontotemporal lobar degeneration and TAR DNA-binding protein 43 inclusions (FTLD-TDP; OR 0.26, p < 0.001). Our study identifies TMEM106B as the first genetic factor modifying disease presentation in C9ORF72 expansion carriers. Homozygosity for the minor allele protects carriers from developing FTD, but not from developing MND; similar effects are seen in FTLD-TDP patients with yet unknown genetic causes. These new findings show that the protective effects of TMEM106B are not confined to carriers of GRN mutations and might be relevant for prognostic testing, and as a promising therapeutic target for the entire spectrum of FTLD-TDP.

Keywords

C9ORF72 TMEM106B Frontotemporal dementia Motor neuron disease Amyotrophic lateral sclerosis Disease modifier 

Notes

Acknowledgments

This project was supported by NIH grants R01 NS080882, R01 NS065782, R01 AG026251, P01 AG017586, P50 NS072187, P50 AG016574, P30 AG013854, P30 AG012300, P30 AG019610, U01 AG006786, the ALS Therapy Alliance, and the Consortium for Frontotemporal Dementia Research. Data collection at the University of British Columbia is supported by CIHR grant #179009. Dr. Van Blitterswijk is supported by the Milton Safenowitz Post-Doctoral Fellowship for ALS research from the ALS Association.

Conflict of interest

Mrs. DeJesus-Hernandez and Dr. Rademakers hold a patent on methods to screen for the hexanucleotide repeat expansion in the C9ORF72 gene; the other authors declare that they have no conflict of interest.

Supplementary material

401_2013_1240_MOESM1_ESM.pdf (251 kb)
Supplementary material 1 (PDF 251 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Marka van Blitterswijk
    • 1
  • Bianca Mullen
    • 1
  • Alexandra M. Nicholson
    • 1
  • Kevin F. Bieniek
    • 1
  • Michael G. Heckman
    • 2
  • Matthew C. Baker
    • 1
  • Mariely DeJesus-Hernandez
    • 1
  • NiCole A. Finch
    • 1
  • Patricia H. Brown
    • 1
  • Melissa E. Murray
    • 1
  • Ging-Yuek R. Hsiung
    • 3
  • Heather Stewart
    • 3
  • Anna M. Karydas
    • 4
  • Elizabeth Finger
    • 5
  • Andrew Kertesz
    • 5
  • Eileen H. Bigio
    • 6
  • Sandra Weintraub
    • 6
  • Marsel Mesulam
    • 6
  • Kimmo J. Hatanpaa
    • 7
  • Charles L. White III
    • 7
  • Michael J. Strong
    • 8
  • Thomas G. Beach
    • 9
  • Zbigniew K. Wszolek
    • 10
  • Carol Lippa
    • 11
  • Richard Caselli
    • 12
  • Leonard Petrucelli
    • 1
  • Keith A. Josephs
    • 13
  • Joseph E. Parisi
    • 13
  • David S. Knopman
    • 13
  • Ronald C. Petersen
    • 13
  • Ian R. Mackenzie
    • 14
  • William W. Seeley
    • 4
  • Lea T. Grinberg
    • 4
  • Bruce L. Miller
    • 4
  • Kevin B. Boylan
    • 10
  • Neill R. Graff-Radford
    • 10
  • Bradley F. Boeve
    • 13
  • Dennis W. Dickson
    • 1
  • Rosa Rademakers
    • 1
    Email author
  1. 1.Department of NeuroscienceMayo ClinicJacksonvilleUSA
  2. 2.Section of BiostatisticsMayo ClinicJacksonvilleUSA
  3. 3.Division of NeurologyUniversity of British ColumbiaVancouverCanada
  4. 4.Department of NeurologyUniversity of CaliforniaSan FranciscoUSA
  5. 5.The University of Western OntarioLondonCanada
  6. 6.Cognitive Neurology and Alzheimer’s Disease CenterNorthwestern University Feinberg School of MedicineChicagoUSA
  7. 7.University of Texas Southwestern Medical CenterDallasUSA
  8. 8.Molecular Brain Research Group, Robarts Research InstituteLondonCanada
  9. 9.Banner Sun Health Research InstituteSun CityUSA
  10. 10.Department of NeurologyMayo ClinicJacksonvilleUSA
  11. 11.Department of NeurologyDrexel University College of MedicinePhiladelphiaUSA
  12. 12.Department of NeurologyMayo ClinicPhoenixUSA
  13. 13.Department of NeurologyMayo ClinicRochesterUSA
  14. 14.Department of Pathology and Laboratory MedicineUniversity of British ColumbiaVancouverCanada

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