Frontotemporal Lobar Degeneration with Ubiquitin-Positive Inclusions: A Molecular Genetic Update

Zee, Julie van der; Gijselinck, Ilse; Pirici, Daniel; Kumar‐Singh, Samir; Cruts, Marc; Broeckhoven, Christine Van

doi:10.1159/000101847

Cited by 21 publications

(13 citation statements)

References 95 publications

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“…The intronic variant IVS2 ?7 G [ A has been identified in one patient, this variant was already listed in the first reported GRN screens ( Van der Zee et al 2007;Sleegers et al 2008), and it was observed to have a low frequency both in patients and controls. We did not find this mutation in 210 controls.…”

Section: Resultsmentioning

confidence: 71%

Progranulin Genetic Screening in Frontotemporal Lobar Degeneration Patients From Central Italy

et al. 2011

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Recently, mutations in the progranulin gene (GRN) were reported to account for the vast majority of Frontotemporal lobar Degeneration (FTLD) and a growing number of reports describe the implication of this gene in the development of the FTLD pathology with a significant variation in clinical features. To better clarify the contribution of GRN mutations to Italian FTLD, we screened 381 subjects: 171 cases and 210 healthy subjects, all from Central Italy, particularly of Tuscan origins. GRN gene was analyzed using High Resolution Melting Analysis and automated Genetic Analyzer. Human Progranulin ELISA Kit was employed to determine the plasma progranulin levels. The screening showed a total of six genetic variants in the GRN gene: 3 pathogenic and 3 non pathogenic in 13 out of 171 patients. The rare intronic variant IVS2 +7 G > A was found in one patient. The pathogenetic mutation, p.T272SfsX10, is confirmed as the most common GRN mutation in Italian FTLD patients with a frequency in our study of 2.32%. Moreover, we identified the first Italian patient with the p.R493X mutation, to date described in 43 families worldwide. Our data report, for the first time, the occurrence of GRN mutations in Tuscany, Central Italy, confirming that genetic variations in this gene could be a considerable genetic cause of FTLD and that genetic screening might be useful both in familial and sporadic FTLD patients.

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Section: Resultsmentioning

confidence: 71%

Progranulin Genetic Screening in Frontotemporal Lobar Degeneration Patients From Central Italy

et al. 2011

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“…The identification of a common genetic cause and subsequent pathological manifestation in both FTLD and ALS provided concrete evidence that these two diseases exist as a part of a common disease spectrum. C9orf72 and GRN mutations likely account for over half of all familial occurrences of FTLD-TDP; however, mutations in the genes encoding tank-binding kinase 1 ( TBK1) and the valosin containing protein ( VCP) have also been discovered as less common genetic causes in patients with FTLD-TDP [20, 23, 46, 54, 77, 84]. In rare cases of FTLD-U, the ubiquitinated protein is a TDP-43 protein family member known as fused in sarcoma (FUS) [50, 67], but there is no known genetic cause for this pathological subtype.…”

Section: Introductionmentioning

confidence: 99%

What we know about TMEM106B in neurodegeneration

2016

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Frontotemporal lobar degeneration is a neurodegenerative disorder affecting over 50,000 people in the United States alone. The most common pathological subtype of FTLD is the presence of ubiquitinated TAR DNA binding protein 43 (TDP-43) accumulations in frontal and temporal brain regions at autopsy. While some cases of FTLD-TDP can be attributed to the inheritance of disease-causing mutations, the majority of cases arise with no known genetic cause. In 2010, the first genome-wide association study (GWAS) was conducted in patients with FTLD-TDP to determine potential genetic risk factors for this homogenous subgroup of dementia patients, leading to the identification of the TMEM106B locus on chromosome 7. In this manuscript, we review the initial discovery and replication studies describing TMEM106B variants as disease risk factors and modifiers in TDP-43 proteinopathies, such as FTLD-TDP caused by progranulin (GRN) or C9orf72 mutations, as well as Alzheimer’s disease and hippocampal sclerosis. We further summarize what is currently known about the previously uncharacterized TMEM106B protein and its role as a potential regulator of lysosomal function, and we discuss how modifying TMEM106B levels might uncover promising therapeutic strategies for individuals suffering from TDP-43 proteinopathy.

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“…A significant proportion of frontotemporal lobar degeneration (FTLD) with transactive response (TAR) DNA-binding protein of 43kDa (TDP-43) proteinopathy (FTLD-TDP) cases are familial [1][2][3][4][5][6][7][8]. Various genetic defects have been identified in these cases, the majority being caused by mutation of the progranulin (GRN) gene [2][3][4][5][6][7][8][9].…”

Section: Introductionmentioning

confidence: 99%

“…Various genetic defects have been identified in these cases, the majority being caused by mutation of the progranulin (GRN) gene [2][3][4][5][6][7][8][9]. Familial FTLD-TDP can also be commonly caused by chromosome 9 open reading frame 72 (C9ORF72) gene [10,11] and more rarely by valosincontaining protein (VCP) gene mutation [12].…”

Section: Introductionmentioning

confidence: 99%

Cortical degeneration in frontotemporal lobar degeneration with TDP-43 proteinopathy caused byprogranulingene mutation

Armstrong

2014

International Journal of Neuroscience

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Familial frontotemporal lobar degeneration with transactive response (TAR) DNA-binding protein of 43 kDa (TDP-43) proteinopathy (FTLD-TDP) is most commonly caused by progranulin (GRN) gene mutation. To characterize cortical degeneration in these cases, changes in density of the pathology across the cortical laminae of the frontal and temporal lobe were studied in seven cases of FTLD-TDP with GRN mutation using quantitative analysis and polynomial curve fitting. In 50% of gyri studied, neuronal cytoplasmic inclusions (NCI) exhibited a peak of density in the upper cortical laminae. Most frequently, neuronal intranuclear inclusions (NII) and dystrophic neurites (DN) exhibited a density peak in lower and upper laminae, respectively, glial inclusions (GI) being distributed in low densities across all laminae. Abnormally enlarged neurons (EN) were distributed either in the lower laminae or were more uniformly distributed across the cortex. The distribution of all neurons present varied between cases and regions, but most commonly exhibited a bimodal distribution, density peaks occurring in upper and lower laminae. Vacuolation primarily affected the superficial laminae and density of glial cell nuclei increased with distance across the cortex from pia mater to white matter. The densities of the NCI, GI, NII, and DN were not spatially correlated. The laminar distribution of the pathology in GRN mutation cases was similar to previously reported sporadic cases of FTLD-TDP. Hence, pathological changes initiated by GRN mutation, and by other causes in sporadic cases, appear to follow a parallel course resulting in very similar patterns of cortical degeneration in FTLD-TDP.

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Frontotemporal Lobar Degeneration with Ubiquitin-Positive Inclusions: A Molecular Genetic Update

Cited by 21 publications

References 95 publications

Progranulin Genetic Screening in Frontotemporal Lobar Degeneration Patients From Central Italy

Progranulin Genetic Screening in Frontotemporal Lobar Degeneration Patients From Central Italy

What we know about TMEM106B in neurodegeneration

Cortical degeneration in frontotemporal lobar degeneration with TDP-43 proteinopathy caused byprogranulingene mutation

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