To ascertain the frequency of inherited FTLD and develop validated pedigree classification criteria for FTLD that provide a standardized means to evaluate pedigree information and insight into the likelihood of mutation-positive genetic test results for C9orf72, MAPT, and GRN.
Loss-of-function progranulin gene (GRN) mutations have been identified as the major cause of frontotemporal lobar degeneration with transactive response (TAR) DNA-binding protein 43 (TDP-43) pathology (frontotemporal lobar degeneration [FTLD]-TDP); however, little is known about the association between progranulin (PGRN) deficiency and neuronal loss in individuals with FTLD-TDP.
The aim of this study was to determine the prevalence of C9orf72 G<sub>4</sub>C<sub>2</sub>-repeat expansion in a Turkish population with FTLD and to determine its effects on the phenotype.
For these studies, we took a departure from traditional immunohistochemical approaches and instead employed immunoassays to quantitatively measure poly(GP) and poly(GA) levels in cerebellum, frontal cortex, motor cortex, and/or hippocampus from 55 C9ORF72 mutation carriers [12 patients with ALS, 24 with frontotemporal lobar degeneration (FTLD) and 19 with FTLD with motor neuron disease (FTLD-MND)].
Mutations resulting in progranulin (PGRN) haploinsufficiency cause frontotemporal lobar degeneration with TDP-43-positive inclusions (FTLD-TDP), a devastating neurodegenerative disease.
Mutations in the progranulin (PGRN) gene have recently been identified in families with frontotemporal lobar degeneration and ubiquitin-positive brain inclusions linked to chromosome 17q21.
A hexanucleotide repeat expansion within a non-coding region of the C9ORF72 gene is the most common mutation causative of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS).
In contrast, the HpScl groups (HpScl and HpScl-AD) were more likely to exhibit genetic variants in GRN and TMEM106B that are associated with frontotemporal lobar degeneration.
Of the remaining patients without mutations but with a strong family history, 7 had pathologic confirmation, falling into 2 groups: type 3 FTLD-TDP without GRN mutations (6) and FTLD-UPS (1).
Mutations in progranulin gene (GRN) are a common cause of autosomal dominant frontotemporal lobar degeneration syndromes and are associated with a wide phenotypic heterogeneity.
Several familial cases of FTLD-U, however, are now known to have mutations in the progranulin (GRN) gene, but granulin is not a component of the TDP-43- and ub-ir inclusions.
A hexanucleotide repeat expansion in chromosome 9 open reading frame 72 (C9ORF72) gene has recently been described as a cause of familial and sporadic frontotemporal lobar degeneration.
The most common inherited form of Frontotemporal Lobar Degeneration (FTLD) known stems from Progranulin (GRN) mutation and exhibits TDP-43 plus ubiquitin aggregates.
Mutations in the progranulin gene (GRN), causative for Frontotemporal Lobar Degeneration with ubiquitin-immunoreactive neuronal inclusions (FTLD-U), could also be associated with Alzheimer's disease (AD).
We further identified a significant association of TMEM106B SNPs with plasma GRN levels in controls (top SNP rs1990622, corrected p = 0.002) and in peripheral blood samples a highly significant correlation was observed between TMEM106B and GRN mRNA expression in patients with FTLD (r = -0.63, p = 7.7 × 10(-5)) and controls (r = -0.49, p = 2.2 × 10(-10)).
The majority of familial FTLD cases are caused by mutations within Microtubule-Associated Protein Tau (MAPT) gene, leading to FTLD-TAU, or Progranulin (PGRN) gene, leading to FTLD-TDP.
Heterozygous mutations in GRN are a major cause of frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP), the second most common early-onset dementia.
Of the TDP-43-positive cases, about 20-30% showed neocortical TDP-43 pathology resembling the FTLD-U subtype associated with progranulin gene (PGRN) mutations.
To identify clinicopathological differences between frontotemporal lobar degeneration (FTLD) due to mutations in progranulin (FTLD-GRN) and chromosome 9 open reading frame 72 (FTLD-C9ORF72).
A morphometric study of the spatial patterns of TDP-43 immunoreactive neuronal inclusions in frontotemporal lobar degeneration (FTLD) with progranulin (GRN) mutation.