However, it is unclear whether some rare FTD-related GRN variants are pathogenic and whether neurodegenerative disorders other than FTD can also be caused by GRN mutations.
Multiple genome-wide association studies have shown that risk of FTD in GRN mutation carriers is modified by polymorphisms in TMEM106B, which encodes a lysosomal membrane protein.
Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) is associated with mutations in the Microtubule-Associated Protein Tau(MAPT) gene or the Progranulin(PGRN) gene.
We identified 9 potentially pathogenic mutations in the AD-causal genes APP, PSEN1, PSEN2, and 6 mutations in a group of non-AD dementia-causal genes including the FTD-causal gene GRN and the VaD-causal gene NOTCH3.
In conclusion, the PGRN Gly35fs mutation causes frontotemporal dementia with variable clinical presentation in a large Swedish family, most likely through nonsense-mediated decay of mutant PGRN mRNA and resulting haploinsufficiency.
The progranulin gene (GRN) g.10325_10331delCTGCTGT (relative to nt1 in NG_007886.1), alias Cys157LysfsX97, has been so far reported only once in a patient with frontotemporal dementia.
Parkinsonism can be the presenting feature of frontotemporal dementia due to Progranulin (GRN) mutations or develop over the course of the disease, mimicking idiopathic Parkinson's disease or atypical parkinsonism.
Nine mutation carriers (age 51.5 ± 13.5 years) and 11 noncarriers (age 52.7 ± 9.5 years) from 5 families with FTD due to GRN mutations underwent brain scanning with FDG-PET and MRI and clinical evaluation.
The clinical profile associated with PGRN mutations constituted, in some patients, a prototypical picture of FTD and in others one of PNFA, both profiles occurring within the same family.
The GRN risk SNP (rs5848_T) was associated with a pattern of atrophy in the dorsomedial frontal lobes bilaterally, remarkable since GRN is a risk factor for frontotemporal dementia.
In this longitudinal study, 58 subjects were identified who had at least two MRI and MAPT mutations (n = 21), GRN mutations (n = 11), C9ORF72 repeat expansions (n = 11) or sporadic FTD (n = 15).
Poorer performance on these tests in asymptomatic PGRN mutation carriers may reflect a prodromal phase preceding the onset of clinically significant symptoms of FTD.
Mutations in the Progranulin gene (PGRN) recently have been discovered to be associated with frontotemporal dementia (FTD) linked to 17q21 without identified MAPT mutations.
The objective of this work was to elucidate the association between PGRN deficiency, WNT5A signalling and cell proliferation in immortalized lymphoblasts from carriers of the c.709-1G > A GRN mutation (asymptomatic and FTLD-TDP).
We hypothesized a higher risk for the latter with immanent neurologic diseases and studied this potential interrelationship in progranulin-deficient mice, which are a model for frontotemporal dementia, a disease dominated by behavioral abnormalities in humans.
The clinical and neuropathologic features of frontotemporal dementia with parkinsonism linked to chromosome 17 and the nature of the mutations in the progranulin and microtubule-associated protein tau genes are emphasized.
To this end, we differentiated 9 induced pluripotent stem cell lines derived from a control subject, a sporadic FTD case and an FTD patient with progranulinS116X mutation.