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Extended FTLD pedigree segregating a Belgian GRN-null mutation: neuropathological heterogeneity in one family.

ABSTRACT: BACKGROUND:In this paper, we describe the clinical and neuropathological findings of nine members of the Belgian progranulin gene (GRN) founder family. In this family, the loss-of-function mutation IVS1?+?5G?>?C was identified in 2006. In 2007, a clinical description of the mutation carriers was published that revealed the clinical heterogeneity among IVS1?+?5G?>?C carriers. We report our comparison of our data with the published clinical and neuropathological characteristics of other GRN mutations as well as other frontotemporal lobar degeneration (FTLD) syndromes, and we present a review of the literature. METHODS:For each case, standardized sampling and staining were performed to identify proteinopathies, cerebrovascular disease, and hippocampal sclerosis. RESULTS:The neuropathological substrate in the studied family was compatible in all cases with transactive response DNA-binding protein (TDP) proteinopathy type A, as expected. Additionally, most of the cases presented also with primary age-related tauopathy (PART) or mild Alzheimer's disease (AD) neuropathological changes, and one case had extensive Lewy body pathology. An additional finding was the presence of cerebral small vessel changes in every patient in this family. CONCLUSIONS:Our data show not only that the IVS1?+?5G?>?C mutation has an exclusive association with FTLD-TDP type A proteinopathy but also that other proteinopathies can occur and should be looked for. Because the penetrance rate of the clinical phenotype of carriers of GRN mutations is age-dependent, further research is required to investigate the role of co-occurring age-related pathologies such as AD, PART, and cerebral small vessel disease.

SUBMITTER: Sieben A

PROVIDER: S-EPMC6389176 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Extended FTLD pedigree segregating a Belgian GRN-null mutation: neuropathological heterogeneity in one family.

Sieben Anne A Van Mossevelde Sara S Wauters Eline E Engelborghs Sebastiaan S van der Zee Julie J Van Langenhove Tim T Santens Patrick P Praet Marleen M Boon Paul P Miatton Marijke M Van Hoecke Sofie S Vandenbulcke Mathieu M Vandenberghe Rik R Cras Patrick P Cruts Marc M De Deyn Peter Paul PP Van Broeckhoven Christine C Martin Jean-Jacques JJ

Alzheimer's research & therapy 20180122 1

<h4>Background</h4>In this paper, we describe the clinical and neuropathological findings of nine members of the Belgian progranulin gene (GRN) founder family. In this family, the loss-of-function mutation IVS1 + 5G > C was identified in 2006. In 2007, a clinical description of the mutation carriers was published that revealed the clinical heterogeneity among IVS1 + 5G > C carriers. We report our comparison of our data with the published clinical and neuropathological characteristics of other GR ...[more]

PMID: 29370838

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Project description:TAR DNA-binding protein 43 (TDP-43) inclusions are pathological hallmarks of patients with frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Loss of TDP-43 in zebrafish engenders a severe muscle and vascular phenotype with a concomitant elevation of filamin C (FLNC) levels, an observation confirmed in the frontal cortex of FTLD-TDP patients. Here, we aimed to further assess the contribution of FLNC to frontotemporal dementia (FTD) etiology. We conducted a mutational screening of FLNC in a cohort of 529 unrelated Belgian FTD and FTD-ALS patients, and a control cohort of 920 unrelated and age-matched individuals. Additionally we performed an in-depth characterization of FLNC expression levels in FTD patients and a murine FTD model.In total 68 missense variants were identified of which 19 (MAF?<?1%) were patient-only. Gene burden analysis demonstrated a significant association between the presence of rare variants in FLNC and disease (P?=?0.0349, RR?=?1.46 [95% CI 1.03-2.07]). Furthermore, elevated FLNC expression levels, observed previously in FTLD-TDP patients, were mainly attributable to FTD patients with the progranulin (GRN) p.0(IVS1?+?5G?>?C) loss-of-function mutation. Increased FLNC levels were, to a lesser extent, also identified in a FLNC p.V831I variant carrier and in FTD patients with the p.R159H mutation in valosin-containing protein (VCP). The GRN-associated increase of FLNC was confirmed in the frontal cortex of aged Grn knockout mice starting at 16-18 months of age. Combined quantitative proteomic and bioinformatic analyses of the frontal cortex of FTD patients possessing elevated FLNC levels, identified multiple altered protein factors involved in accelerated aging, neurodegeneration and synaptogenesis.Our findings further support the involvement of aberrant FLNC expression levels in FTD pathogenesis. Identification of increased FLNC levels in aged Grn mice and impaired pathways related to aging and neurodegeneration, implies a potential role for FLNC in mediating or accelerating the aging process.

Dataset Information

Extended FTLD pedigree segregating a Belgian GRN-null mutation: neuropathological heterogeneity in one family.

Publications

Extended FTLD pedigree segregating a Belgian GRN-null mutation: neuropathological heterogeneity in one family.

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