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

Topic: Brain proteins, microglia and lab models

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.

@article{cruts2006-16862115,
  author  = {Cruts, M. and Gijselinck, I. and van der Zee, J. and Engelborghs, S. and Wils, H. and Pirici, D. and Rademakers, R. and others},
  title   = {{Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21}},
  journal = {Nature},
  year    = {2006},
  doi     = {10.1038/nature05017},
  pmid    = {16862115},
  url     = {https://doi.org/10.1038/nature05017}
}

Key findings

• 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.

Why it matters

This study found that mutations in the progranulin gene (PGRN) cause frontotemporal dementia linked to chromosome 17q21, with loss of the mutant allele and reduced PGRN expression. It provides genetic evidence that reduced PGRN-mediated neuronal survival leads to neurodegeneration, but no treatment was tested.

Study details

• Participants17
• Evidence strengthLow

Read the original

• DOI: 10.1038/nature05017
• PubMed: 16862115
• Original source →

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Studies this one cites

Referenced by this study and also in the alzhub library, so you can read them here.

• Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17 Nature · 1998-06-01 · usefulness score 64/100 · Lewy body dementia
• Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria Neurology · 1998-12-01 · usefulness score 62/100 · Lewy body dementia
• Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17 Nature · 2006-07-16 · usefulness score 61/100 · Lewy body dementia
• Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein Nature genetics · 2004-03-21 · usefulness score 58/100 · Lewy body dementia
• Clinical and pathological diagnosis of frontotemporal dementia: report of the Work Group on Frontotemporal Dementia and Pick's Disease Archives of neurology · 2001-11-01 · usefulness score 56/100 · Getting a diagnosis
• Frontotemporal dementia: clinicopathological correlations Annals of neurology · 2006-06-01 · usefulness score 55/100 · Getting a diagnosis
• Familial frontotemporal dementia with ubiquitin-positive inclusions is linked to chromosome 17q21-22 Brain : a journal of neurology · 2001-10-01 · usefulness score 45/100 · Digital health tools

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