A novel mutation P112H in the TARDBP gene associated with frontotemporal lobar degeneration without motor neuron disease and abundant neuritic amyloid plaques

Abstract

Introduction: Although TDP-43 is the main constituent of the ubiquitinated cytoplasmic inclusions in the most common forms of frontotemporal lobar degeneration, TARDBP mutations are not a common cause of familial frontotemporal dementia, especially in the absence of motor neuron disease.

Results: We describe a pedigree presenting with a complex autosomal dominant disease, with a heterogeneous clinical phenotype, comprising unspecified dementia, parkinsonism, frontotemporal dementia and motor neuron disease. Genetic analyses identified a novel P112H TARDBP double variation located in exon 3 coding for the first RNA recognition motif of the protein (RRM1). This double mutation is probably pathogenic based on neuropathological findings, in silico prediction analysis and exome sequencing. The two autopsied siblings described here presented with frontotemporal dementia involving multiple cognitive domains and behavior but lacking symptoms of motor neuron disease throughout the disease course. The siblings presented with strikingly similar, although atypical, neuropathological features, including an unclassifiable TDP-43 inclusion pattern, a high burden of tau-negative β-amyloid neuritic plaques with an AD-like biochemical profile, and an unclassifiable 4-repeat tauopathy. The co-occurrence of multiple protein inclusions points to a pathogenic mechanism that facilitates misfolded protein interaction and aggregation or a loss of TDP-43 function that somehow impairs protein clearance.

Conclusions: TARDBP mutation screening should be considered in familial frontotemporal dementia cases, even without signs or symptoms of motor neuron disease, especially when other more frequent causes of genetic frontotemporal dementia (i.e. GRN, C9ORF72, MAPT) have been excluded and when family history is complex and includes parkinsonism, motor neuron disease and frontotemporal dementia. Further investigations in this family may provide insight into the physiological functions of TARDBP.

Figure 1

Simplified pedigree. For simplification, the number of siblings is depicted inside the diamond shape in generation III representing the number of siblings indicated inside. Circle: female; square: male; diagonal lines: deceased; open symbols: unaffected; ALS: amyotrophic lateral sclerosis. FTD: frontotemporal dementia. PDD: Parkinson’s disease with dementia; “d”: age at death.

Figure 2

Magnetic resonance imaging (MRI) of index patient. (a) T1 axial sequences, showing prominent atrophy, right predominant, affecting frontal, temporal, insular and parietal lobes, present in the first evaluation (4 years after clinical onset). (b) Similar but more pronounced findings one year later. Positron emission tomography (PET) images of the proband. 18 F-FDG PET (c) showed pronounced hypometabolism in the right frontal, temporal and parietal cortex, while Aβ-PET (11C-PIB, d) showed elevated cortical retention bilaterally. MRI images are shown in radiological orientation and PET images in neurological orientation SUVR – standardized uptake value ratio (t- = 30-60 min, normalized to mean activity in the pons); DVR – Distribution Volume Ratio (0–90 min, Logan graphical analysis, reference region = cerebellum gray matter).

Figure 3

Pathological TDP -43 inclusions in the index and patient 2. (a) inferior temporal gyrus shows abundant neuronal cytoplasmic inclusions, some threads and intranuclear inclusions (* and insert). (b) orbitofrontal cortex of the same patient showing similar features. (c) ventral striatum of patient 2 depicting neuronal cytoplasmic inclusions and few threads. (d) inferior temporal gyrus of patient 2. The neuronal cytoplasmic inclusions present in different shapes, either compact (arrow) or granular (arrowhead) in nature. Inclusions are found throughout the cortical layers. Scale bars: 10 μm.

Figure 4

Histopathological features of the proband and patient 2. Right column (a, d) immunostaining for beta-amyloid (4G8), middle column (b , e), immunostaining for phospho-tau (CP-13), and left column (c, f) Gallays silver staining. (a, b) proband showing abundant neuritic plaques including cored plaques in angular gyrus. The plaques are negative for phospho-tau, in contrast to those seen in Alzheimer’s disease. Despite the lack of phospho-tau, the silver staining confirm the plaques’ neuritic nature (c). (d- f) The same features are seen in the middle frontal gyrus of patient 2. Scale bars: 40 μm.

Figure 5

Atypical 4R- tauopathy of the proband and patient 2. Left column (a, c) immunostaining for 4R-tau, and right column (b, d), immunostaining for 3R-tau. All sections are from entorhinal cortex. (a and b) proband showing 4R-tau glial inclusions, threads and few neuronal tangles in entorhinal cortex (a); only a neurofibrillary tangles (arrow) is 3R-tau-positive pathology in the same area (b). The same features are seen in patient 2 (c, d) to a lesser extent. Scale bars: 10 μm.

Figure 6

Comparison of Aß patterns between different human brain samples. The relative abundance of different variants of Aß in detergent preparations from human temporal lobe samples was analyzed by urea-SDS-PAGE/immunoblot. For comparison, the indicated synthetic Aß peptides were loaded (S). P2, P1, AD1, AD2 temporal lobe samples from proband (P1), patient 2 (P2) and two Alzheimer’s disease (AD1 and AD2) patients. Aß immunoblots of the detergent fractions probed with mAb 6E10. 5 μg of total protein of each sample was loaded.