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

Marc Cruts, Ilse Gijselinck, Julie Van Der Zee, Sebastiaan Engelborghs, Hans Wils, Daniel Pirici, Rosa V Rademakers, Rik Vandenberghe, Bart Dermaut, Jean Jacques Martin, Cornelia Van Duijn, Karin Peeters, Raf Sciot, Patrick Santens, Tim De Pooter, Maria Mattheijssens, Marleen Van Den Broeck, Ivy Cuijt, Krist'l Vennekens, Peter P. De DeynSamir Kumar-Singh, Christine Van Broeckhoven

Research output: Contribution to journalArticle

1032 Citations (Scopus)

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). FTDU-17 patients have consistently been shown to lack a tau-immunoreactive pathology, a feature characteristic of FTD with parkinsonism linked to mutations in MAPT (FTDP-17). Furthermore, in FTDU-17 patients, mutations in MAPT and genomic rearrangements in the MAPT region have been excluded by both genomic sequencing and fluorescence in situ hybridization on mechanically stretched chromosomes. 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 tumorigenesis. Besides the production of truncated PGRN proteins due to premature stop codons, 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 family. 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.

Original languageEnglish (US)
Pages (from-to)920-924
Number of pages5
JournalNature
Volume442
Issue number7105
DOIs
StatePublished - Aug 24 2006
Externally publishedYes

Fingerprint

Frontotemporal Dementia
Microtubule-Associated Proteins
Chromosomes
Mutation
Alleles
Physiological Phenomena
Haploinsufficiency
Intranuclear Inclusion Bodies
RNA Splice Sites
Initiator Codon
Nonsense Codon
Inclusion Bodies
Pathologic Processes
Ubiquitin
Fluorescence In Situ Hybridization
Introns
Dementia
Intercellular Signaling Peptides and Proteins
Carcinogenesis
Proteins

ASJC Scopus subject areas

  • General

Cite this

Cruts, M., Gijselinck, I., Van Der Zee, J., Engelborghs, S., Wils, H., Pirici, D., ... Van Broeckhoven, C. (2006). Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature, 442(7105), 920-924. https://doi.org/10.1038/nature05017

Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. / Cruts, Marc; Gijselinck, Ilse; Van Der Zee, Julie; Engelborghs, Sebastiaan; Wils, Hans; Pirici, Daniel; Rademakers, Rosa V; Vandenberghe, Rik; Dermaut, Bart; Martin, Jean Jacques; Van Duijn, Cornelia; Peeters, Karin; Sciot, Raf; Santens, Patrick; De Pooter, Tim; Mattheijssens, Maria; Van Den Broeck, Marleen; Cuijt, Ivy; Vennekens, Krist'l; De Deyn, Peter P.; Kumar-Singh, Samir; Van Broeckhoven, Christine.

In: Nature, Vol. 442, No. 7105, 24.08.2006, p. 920-924.

Research output: Contribution to journalArticle

Cruts, M, Gijselinck, I, Van Der Zee, J, Engelborghs, S, Wils, H, Pirici, D, Rademakers, RV, Vandenberghe, R, Dermaut, B, Martin, JJ, Van Duijn, C, Peeters, K, Sciot, R, Santens, P, De Pooter, T, Mattheijssens, M, Van Den Broeck, M, Cuijt, I, Vennekens, K, De Deyn, PP, Kumar-Singh, S & Van Broeckhoven, C 2006, 'Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21', Nature, vol. 442, no. 7105, pp. 920-924. https://doi.org/10.1038/nature05017
Cruts M, Gijselinck I, Van Der Zee J, Engelborghs S, Wils H, Pirici D et al. Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature. 2006 Aug 24;442(7105):920-924. https://doi.org/10.1038/nature05017
Cruts, Marc ; Gijselinck, Ilse ; Van Der Zee, Julie ; Engelborghs, Sebastiaan ; Wils, Hans ; Pirici, Daniel ; Rademakers, Rosa V ; Vandenberghe, Rik ; Dermaut, Bart ; Martin, Jean Jacques ; Van Duijn, Cornelia ; Peeters, Karin ; Sciot, Raf ; Santens, Patrick ; De Pooter, Tim ; Mattheijssens, Maria ; Van Den Broeck, Marleen ; Cuijt, Ivy ; Vennekens, Krist'l ; De Deyn, Peter P. ; Kumar-Singh, Samir ; Van Broeckhoven, Christine. / Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. In: Nature. 2006 ; Vol. 442, No. 7105. pp. 920-924.
@article{1b776b8ec48c48709964606608cb7b38,
title = "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). FTDU-17 patients have consistently been shown to lack a tau-immunoreactive pathology, a feature characteristic of FTD with parkinsonism linked to mutations in MAPT (FTDP-17). Furthermore, in FTDU-17 patients, mutations in MAPT and genomic rearrangements in the MAPT region have been excluded by both genomic sequencing and fluorescence in situ hybridization on mechanically stretched chromosomes. 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 tumorigenesis. Besides the production of truncated PGRN proteins due to premature stop codons, 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 family. 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.",
author = "Marc Cruts and Ilse Gijselinck and {Van Der Zee}, Julie and Sebastiaan Engelborghs and Hans Wils and Daniel Pirici and Rademakers, {Rosa V} and Rik Vandenberghe and Bart Dermaut and Martin, {Jean Jacques} and {Van Duijn}, Cornelia and Karin Peeters and Raf Sciot and Patrick Santens and {De Pooter}, Tim and Maria Mattheijssens and {Van Den Broeck}, Marleen and Ivy Cuijt and Krist'l Vennekens and {De Deyn}, {Peter P.} and Samir Kumar-Singh and {Van Broeckhoven}, Christine",
year = "2006",
month = "8",
day = "24",
doi = "10.1038/nature05017",
language = "English (US)",
volume = "442",
pages = "920--924",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7105",

}

TY - JOUR

T1 - Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21

AU - Cruts, Marc

AU - Gijselinck, Ilse

AU - Van Der Zee, Julie

AU - Engelborghs, Sebastiaan

AU - Wils, Hans

AU - Pirici, Daniel

AU - Rademakers, Rosa V

AU - Vandenberghe, Rik

AU - Dermaut, Bart

AU - Martin, Jean Jacques

AU - Van Duijn, Cornelia

AU - Peeters, Karin

AU - Sciot, Raf

AU - Santens, Patrick

AU - De Pooter, Tim

AU - Mattheijssens, Maria

AU - Van Den Broeck, Marleen

AU - Cuijt, Ivy

AU - Vennekens, Krist'l

AU - De Deyn, Peter P.

AU - Kumar-Singh, Samir

AU - Van Broeckhoven, Christine

PY - 2006/8/24

Y1 - 2006/8/24

N2 - 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). FTDU-17 patients have consistently been shown to lack a tau-immunoreactive pathology, a feature characteristic of FTD with parkinsonism linked to mutations in MAPT (FTDP-17). Furthermore, in FTDU-17 patients, mutations in MAPT and genomic rearrangements in the MAPT region have been excluded by both genomic sequencing and fluorescence in situ hybridization on mechanically stretched chromosomes. 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 tumorigenesis. Besides the production of truncated PGRN proteins due to premature stop codons, 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 family. 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.

AB - 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). FTDU-17 patients have consistently been shown to lack a tau-immunoreactive pathology, a feature characteristic of FTD with parkinsonism linked to mutations in MAPT (FTDP-17). Furthermore, in FTDU-17 patients, mutations in MAPT and genomic rearrangements in the MAPT region have been excluded by both genomic sequencing and fluorescence in situ hybridization on mechanically stretched chromosomes. 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 tumorigenesis. Besides the production of truncated PGRN proteins due to premature stop codons, 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 family. 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.

UR - http://www.scopus.com/inward/record.url?scp=33746910649&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33746910649&partnerID=8YFLogxK

U2 - 10.1038/nature05017

DO - 10.1038/nature05017

M3 - Article

C2 - 16862115

AN - SCOPUS:33746910649

VL - 442

SP - 920

EP - 924

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7105

ER -