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Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21

Abstract

Frontotemporal dementia (FTD) with ubiquitin-immunoreactive neuronal inclusions (both cytoplasmic and nuclear) of unknown nature has been linked to a chromosome 17q21 region (FTDU-17) containing MAPT (microtubule-associated protein tau)1,2,3. FTDU-17 patients have consistently been shown to lack a tau-immunoreactive pathology1,2,3, a feature characteristic of FTD with parkinsonism linked to mutations in MAPT (FTDP-17)4. Furthermore, in FTDU-17 patients, mutations in MAPT and genomic rearrangements in the MAPT region have been excluded by both genomic sequencing5 and fluorescence in situ hybridization on mechanically stretched chromosomes6. Here we demonstrate that FTDU-17 is caused by mutations in the gene coding for progranulin (PGRN), a growth factor involved in multiple physiological and pathological processes including tumorigenesis7. Besides the production of truncated PGRN proteins due to premature stop codons8, we identified a mutation within the splice donor site of intron 0 (IVS0 + 5G > C), indicating loss of the mutant transcript by nuclear degradation. The finding was made within an extensively documented Belgian FTDU-17 founder family3. Transcript and protein analyses confirmed the absence of the mutant allele and a reduction in the expression of PGRN. We also identified a mutation (c.3G > A) in the Met1 translation initiation codon, indicating loss of PGRN due to lack of translation of the mutant allele. Our data provide evidence that PGRN haploinsufficiency leads to neurodegeneration because of reduced PGRN-mediated neuronal survival. Furthermore, in a Belgian series of familial FTD patients, PGRN mutations were 3.5 times more frequent than mutations in MAPT, underscoring a principal involvement of PGRN in FTD pathogenesis.

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Figure 1: FTDU-17 candidate region and PGRN mutations.
Figure 2: Segregation of the PGRN splice donor site mutation IVS0 + 5G > C in Belgian founder family DR8.
Figure 3: Transcript and protein analyses of the PGRN IVS0 + 5G > C mutation.

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Acknowledgements

The authors are grateful to the patients and family members for their kind cooperation in this study, and to the personnel of the VIB Genetic Service Facility (http://www.vibgeneticservicefacility.be) and IBB Biobank. We thank S. Serneels for help with genetic analyses, and E. De Leenheir and B. Van Everbroeck for support with the neuropathology studies. The research described in this paper was supported by the Special Research Fund of the University of Antwerp, the Fund for Scientific Research Flanders (FWO-F), the Interuniversity Attraction Poles program P5/19 of the Belgian Science Policy Office, the International Alzheimer Research Foundation, an EU contract (APOPIS), and a Zenith award of the Alzheimer's Association USA. The FWO-F provided postdoctoral fellowships to M.C., S.E. and R.R., a PhD fellowship to I.G., and clinical investigator award to R.V. J.v.d.Z. is holder of a PhD fellowship of the Institute for Science and Technology Flanders (IWT-F), Belgium. Author Contributions M.C., I.G., J.v.d.Z., R.R., T.D.P., M.V.d.B. and C.V.B. contributed to the genetic and genomic studies; S.E., R.V., B.D., P.S. and P.P.D.D. to the clinical studies and patient collections; S.E., D.P., J.-J.M., R.S., P.P.D.D. and S.K.-S. to the neuropathology studies; I.G., H.W., I.C., K.V., S.K.-S., M.C. and C.V.B. to the transcript and protein expression studies; K.P., M.M. and C.V.B. to the family ascertainment; I.G. and M.C. to the FISH studies; and C.v.D. originally ascertained Dutch family 1083. C.V.B. was responsible for writing the manuscript.

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Correspondence to Christine Van Broeckhoven.

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Cruts, M., Gijselinck, I., van der Zee, J. et al. Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature 442, 920–924 (2006). https://doi.org/10.1038/nature05017

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