Modifiers of GRN -Associated Frontotemporal Lobar Degeneration

Wauters, Eline; Mossevelde, Sara Van; Zee, Julie van der; Cruts, Marc; Broeckhoven, Christine Van

doi:10.1016/j.molmed.2017.08.004

Cited by 28 publications

(22 citation statements)

References 163 publications

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“…The dosage of circulating progranulin sped up the identification of GRN mutations thus favoring genotype-phenotype correlation studies. In GRN null mutation carriers it has been demonstrated that the shortage of progranulin (i) invariably precedes clinical symptoms, since a reduction of protein is also measured in pre-symptomatic subjects (ii) is associated with multiple clinical presentations ranging from behavioral variant of frontotemporal dementia (bvFTD) (the most common clinical presentation), to primary progressive aphasia, corticobasal syndrome, AD, Parkinson's disease or dementia with Lewy bodies phenotype (Le Ber et al, 2008 ; Benussi et al, 2009 ; Arosio et al, 2013 ; Wauters et al, 2017 ).…”

Section: Loss Of Progranulin In Alzheimer's Disease Frontotemporal Dmentioning

confidence: 99%

“…In these disorders, monogenic forms due to a mutation in a single gene are described. However, a broad phenotypic expression variability between or even within pedigrees bearing the same mutation was found in many late onset monogenic neurodegenerative diseases (Finckh et al, 2000a ; Binetti et al, 2003 ; Rademakers et al, 2007 ; Ghidoni et al, 2012a ; Wauters et al, 2017 ). As we hypothesized “environmental/unidentified risk factors show an unexpected deterministic tendency to produce sporadic non-genetically determined forms of the disease in the vast majority of cases.…”

Section: Introductionmentioning

confidence: 99%

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Loss of Neuroprotective Factors in Neurodegenerative Dementias: The End or the Starting Point?

2017

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Recent clinical, genetic and biochemical experimental evidences highlight the existence of common molecular pathways underlying neurodegenerative diseases. In this review, we will explore a key common pathological mechanism, i.e., the loss of neuroprotective factors, across the three major neurodegenerative diseases leading to dementia: Alzheimer's disease (AD), Frontotemporal dementia (FTD) and Lewy body dementia (LBD). We will report evidences that the Brain Derived Neurotrophic Factor (BDNF), the most investigated and characterized brain neurotrophin, progranulin, a multi-functional adipokine with trophic and growth factor properties, and cystatin C, a neuroprotective growth factor, are reduced in AD, FTD, and LBD. Moreover, we will review the molecular mechanism underlying the loss of neuroprotective factors in neurodegenerative diseases leading to dementia, with a special focus on endo-lysosomal pathway and intercellular communication mediated by extracellular vesicles. Exploring the shared commonality of disease mechanisms is of pivotal importance to identify novel potential therapeutic targets and to develop treatments to delay, slow or block disease progression.

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Section: Loss Of Progranulin In Alzheimer's Disease Frontotemporal Dmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Loss of Neuroprotective Factors in Neurodegenerative Dementias: The End or the Starting Point?

2017

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“…Progranulin is implicated in the pathogenesis of rheumatoid arthritis (RA) and other inflammatory diseases. Moreover, the role of PGRN was demonstrated in neurodegenerative and metabolic disorders . It should be noted that little is known about the pathological mechanisms mediating HA; a role for serum PGRN has yet to be addressed.…”

Section: Discussionmentioning

confidence: 99%

Increased serum levels of progranulin (PGRN) in patients with haemophilic arthropathy

Kotela

Łęgosz

Sarzyńska

et al. 2018

Clin Exp Pharma Physio

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Haemophilia A and B are rarely occurring X chromosome-linked congenital coagulation disorders dominated by spontaneous joint bleedings and chronic synovitis, leading to development of haemophilic arthropathy (HA). Progranulin (PGRN) is a growth factor with anti-inflammatory and immunomodulatory properties. PGRN is an important molecule in the pathogenesis of osteoarthritis (OA) and rheumatological disorders. This study was aimed at investigating the potential role of PGRN in the mechanisms underlying the pathogenesis of HA. The serum levels of PGRN were measured by enzyme-linked immunosorbent assay (ELISA) in patients with end-stage knee joint HA (n = 20) and end-stage primary knee joint OA (n = 20) who met the inclusion and exclusion criteria. The clinical and radiological assessment of disease severity was evaluated by the Knee Society Score (KSS) and Kellgren-Lawrence scale. Median PGRN levels in HA patients was 349.1 ng/mL (232.8-415.6 ng/mL) and in OA patients 148.3 ng/mL (112.1-275.3 ng/mL) with statistically significant differences between both groups (P < 0.015). Further analysis revealed no correlation between PGRN levels and any of the patient demographics and clinical parameters. This study demonstrates increased PGRN serum levels in patients with HA and provides new insights into the mechanisms underlying the pathogenesis of HA indicating a new potential target for therapeutic intervention. K E Y W O R D S haemophilia, haemophilic arthropathy, osteoarthritis, progranulin How to cite this article: Kotela A, Wojdasiewicz P, Łęgosz P, et al. Increased serum levels of progranulin (PGRN) in patients with haemophilic arthropathy. Clin Exp Pharmacol Physiol.

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“…Other factors might be conditioning the appearance of the disease, and supporting this is the fact that some studies have nominated genetic modifiers. 43 In addition, the gene is estimated to have 90% penetrance by an advanced age, leaving a small amount of carriers possibly unaffected. 44 In brief, we believe that this particular mutation is responsible for standard FTD and, when both alleles are affected, for mild adult onset NCL.…”

Section: Partially Misdiagnosed Casesmentioning

confidence: 99%

Expanding the Genetic Landscape of Usher-Like Phenotypes

Fuster-García

García‐García

Jaijo

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Usher syndrome (USH) is a rare disorder characterized by retinitis pigmentosa (RP) and sensorineural hearing loss. Several genes are responsible for the disease, but not all cases are explained by mutations in any of these, supporting the fact that there remain other unknown genes that have a role in the syndrome. We aimed to find the genetic cause of presumed USH patients lacking pathogenic mutations in the known USH genes. METHODS. Whole exome sequencing was performed on a priori USH-diagnosed subjects from nine unrelated families, which had shown negative results for an USH-targeted panel in a previous study. RESULTS. We identified possible pathogenic variants in six of the studied families. One patient harbored mutations in REEP6 and TECTA, each gene tentatively causative of one of the two main symptoms of the disease, mimicking the syndrome. In three patients, only the retinal degeneration causative mutations were detected (involving EYS, WDR19, and CNGB1 genes). Another family manifested a dementia-linked retinal dystrophy dependent on an allele dosage in the GRN gene. Last, another case presented a homozygous mutation in ASIC5, a gene not yet associated with USH. CONCLUSIONS. Our findings demonstrate that pending cases should be clinically and genetically carefully assessed, since more patients than expected may be either related phenocopies or affected by a more complex disease encompassing additional symptoms rather than classical USH.

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Modifiers of GRN -Associated Frontotemporal Lobar Degeneration

Cited by 28 publications

References 163 publications

Loss of Neuroprotective Factors in Neurodegenerative Dementias: The End or the Starting Point?

Loss of Neuroprotective Factors in Neurodegenerative Dementias: The End or the Starting Point?

Increased serum levels of progranulin (PGRN) in patients with haemophilic arthropathy

Expanding the Genetic Landscape of Usher-Like Phenotypes

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