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.

Novel progranulin mutations with reduced serum-progranulin levels in frontotemporal lobar degeneration

“…All 13 exons and B60 nucleotides into the flanking intronic sequences in GRN were PCR amplified and sequenced using in-house and previously published primers. 6,7 For haplotype analyses, microsatellites and single-nucleotide polymorphisms (SNPs) in GRN were used ( Table 2). The SNP genotypes were obtained from GRN sequence (A).…”

“…[2][3][4] Up to 50% of FTLD patients have a positive family history for dementia, indicating that genetic factors contribute to the etiology. Mutations in several genes have been shown to cause FTLD and most frequently in the microtubule-associated protein tau 5 (MAPT, OMIM #600274), progranulin 6,7 (GRN, OMIM #607485) and in the recently identified chromosome 9 openreading frame 72 gene 8,9 (C9orf72, OMIM #105550). Mutations in GRN account for 5-10% of all the FTLD cases.…”

Rare variants in β-Amyloid precursor protein (APP) and Parkinson’s disease

“…2 Phenotypically, it is known that at least 30% of individuals with PD develop dementia 5,6 and that age has been described as a major predisposing factor for the development of cognitive impairment. 7 Accordingly, we sought to assess the contribution of genetic factors known to be involved in dementias such as AD [8][9][10][11] or FTD 2,[12][13][14] to the PD phenotype.…”

Progranulin gene variability increases the risk for primary progressive multiple sclerosis in males

“…1 In adult central nervous system, GRN mRNA is expressed in forebrain, olfactory bulbs and spinal cord. 2 Other evidence can be found about increased levels of GRN mRNA in several inflammatory neurodegenerative disorders associated with microglial activation, such as amyotrophic lateral sclerosis 3 and virally induced central nervous system inflammation. 4 A contribution of GRN variability has also been previously shown in sporadic FTLD, 5,6 although another study did not confirm these data.…”