Investigating the role of filamin C in Belgian patients with frontotemporal dementia linked to GRN deficiency in FTLD-TDP brains

Abstract

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.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-015-0246-7) contains supplementary material, which is available to authorized users.

De novo mutations in FLNC leading to early-onset restrictive cardiomyopathy and congenital myopathy

“…The prominent involvement of central nervous system in one of the patients is rather unusual for filaminopathies, nevertheless could take place in the light of a previously published case of FLNC-associated myopathy with cerebellar ataxia and a role of filamin C in development of frontotemporal dementia (Janssens et al, 2015;Tasca et al, 2012;Xie, Xu, Davie, & Chung, 1998). Altogether, our and previously reported data support the hypothesis that FLNC-caused RCM has an early, often childhood, presentation and could be combined with a congenital myopathy accompanied by mild CK elevation.…”

Expanding the central nervous system disease spectrum associated with FLNC mutation

“…We speculate that CNS abnormalities are part of the FLNC phenotype as a consequence of defective neuronal development. Indeed, other studies have shown an association between FLNC and “neuronal” abnormalities …”

Structure and Function of Filamin C in the Muscle Z-Disc

“…Interestingly, the p.A193T mutation is also associated with cerebellar and spinal cord abnormalities [93]. Indeed, other studies have shown an association between FLNC and neuronal diseases [120,123,134]. However, another mutation in the srABD (c.A664G, p.M222V) showed a predominant leg involvement and myofibrillar aggregates [94].…”

“…In humans, a wide variety of myopathy-associated mutations and variants have also demonstrated importance of FLNC in muscle development (Figure 4 and Table 2). 38 variants Hypertrophic Cardiomyopathy [111] 23 truncating mutations Dilated and Arrhythmogenic Cardiomyopathy [112] c.7251+1 G>A c.5669-1delG Dilated cardiomyopathy [113] c.3646T>A, p.Tyr1216Asn (R10) Myofibrillar myopathy [114] c.318C>G, p.Phe106Leu (srABD) c.2971C>T, p.Arg991Ter (R8) Dilated cardiomyopathy [115] c.4871C>T, p.S1624L (R14) c.6478A>T, p.I2160F (R20) Familial Restrictive Cardiomyopathy [116] c.2786-2800del, p.V930-A934del (R7) Limb-girdle muscular dystrophy [117] c.969 + 3 A > G Muscular dystrophy, Congenital myopathy [118] c.3791 -1 G>C Dilated cardiomyopathy [119] p.V831I (R6) Additional 20 variants Pick's disease Frontotemporal dementia [120] c.4824G>A, p.A1539T (R14) 7 additional mutations Familial hypertrophic cardiomyopathy [121] c.7256C>T, p.Thr2419Met (R22) Myofibrillar myopathy with late-onset cerebellar ataxia [122] c.5160delC, p.Phe1720LeufsTer63 (R15) Distal myopathy with upper limb predominance [123] c.577G>A, p.Ala193Thr (srABD) c.752T>C, p.Met251Thr (srABD) Distal myopathy [124] c. 2695-2712 del/GTTTGT ins, p. Lys899-Val904 del, Val899-Cys900 ins (R7) Myofibrillar myopathy [125] c.2997-3008del, p.Val930_Thr933del (R7) Myofibrillar myopathy [126] c.8130G >A, p.Trp2710Ter (R24) Myofibrillar myopathy [14,127,128]…”