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, 118 (5), 633-45

TARDBP 3'-UTR Variant in Autopsy-Confirmed Frontotemporal Lobar Degeneration With TDP-43 Proteinopathy

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TARDBP 3'-UTR Variant in Autopsy-Confirmed Frontotemporal Lobar Degeneration With TDP-43 Proteinopathy

Michael A Gitcho et al. Acta Neuropathol.

Abstract

Pathogenic mutations in the gene encoding TDP-43, TARDBP, have been reported in familial amyotrophic lateral sclerosis (FALS) and, more recently, in families with a heterogeneous clinical phenotype including both ALS and frontotemporal lobar degeneration (FTLD). In our previous study, sequencing analyses identified one variant in the 3'-untranslated region (3'-UTR) of the TARDBP gene in two affected members of one family with bvFTD and ALS and in one unrelated clinically assessed case of FALS. Since that study, brain tissue has become available and provides autopsy confirmation of FTLD-TDP in the proband and ALS in the brother of the bvFTD-ALS family and the neuropathology of those two cases is reported here. The 3'-UTR variant was not found in 982 control subjects (1,964 alleles). To determine the functional significance of this variant, we undertook quantitative gene expression analysis. Allele-specific amplification showed a significant increase of 22% (P < 0.05) in disease-specific allele expression with a twofold increase in total TARDBP mRNA. The segregation of this variant in a family with clinical bvFTD and ALS adds to the spectrum of clinical phenotypes previously associated with TARDBP variants. In summary, TARDBP variants may result in clinically and neuropathologically heterogeneous phenotypes linked by a common molecular pathology called TDP-43 proteinopathy.

Conflict of interest statement

Conflict of interest statement The authors report no conflicts of interest.

Figures

Fig. 1
Fig. 1
TARDBP 3′-UTR missense variant within a highly conserved region of affected members of a family with FTLD and/or MND with TDP-43 proteinopathy. a Protein domain structure of TDP-43. Recognition motifs: NE nuclear export sequence, NL nuclear localization sequence, RRM1 and 2 RNA recognition motifs 1 and 2, and hnRNP heterogeneous nuclear ribonucleoprotein (glycine-rich) domain. b TARDBP genomic structure (blue untranslated region, red coding region) and position of 3′UTR variant. cTARDBP 3′-UTR is evolutionarily conserved between species (nucleotide in red is position of 3′-UTR variant). d Chromatogram of 3′-UTR displays a base-pair change (2,076 G>A, NM_007375.3). e Pedigree of family displaying heterogeneous clinical phenotypes: ALS formula image, bvFTD formula image, MND formula image; arrow proband. No DNA was available from either parent
Fig. 2
Fig. 2
TARDBP expression (upper panel) is increased in FTLD with TARDBP 3′-UTR variant in comparison to normal subjects. TARDBP expression (lower panel) is increased in FTLD with 3′UTR variant compared with other TDP-43 proteinopathies. The values expressed represent the means of at least three independent experiments repeated three times and each normalized to glyceraldehyde 3-phosphate dehydrogenase (GAPDH) mRNA. To compensate for multiple comparisons, a Bonferroni correction was made with the variability expressed as the standard deviation: *P < 0.05; **P < 0.005; ***P < 0.001)
Fig. 3
Fig. 3
Macroscopy of FTLD with TARDBP 3′-UTR variant. a Coronal slice showing moderate atrophy of the frontal pole. b Coronal slice of the frontal lobe showing moderate dilatation of the lateral ventricle. c There is mild pallor of the substantia nigra
Fig. 4
Fig. 4
Microscopy of FTLD with TARDBP 3′-UTR variant. a Mild superficial microvacuolation and gliosis in superficial frontal cortex (H&E, ×100). b Severe neuronal loss and gliosis in the subiculum [glial fibrillary acidic protein (GFAP) immunohistochemistry, ×100]. c Hypoglossal motor neuron with a Bunina body (arrow) and a shrunken motor neuron (arrowhead) (H&E, ×400)
Fig. 5
Fig. 5
Neuronal cytoplasmic inclusions (NCIs) in FTLD with TARDBP 3′-UTR variant. a, b Frequent NCIs are present in the hippocampal dentate gyrus (a ubiquitin, b TDP-43 immunohistochemistry, a, b ×400). c Sparse granular NCIs (arrows) in the superficial temporal cortex (TDP-43 immunohistochemistry, ×400). d Sparse granular NCIs (arrows) in the pyramidal neurons of cortical layer 3 (TDP-43 immunohistochemistry, ×400). e Frequent granular NCIs in the putamen (TDP-43 immunohistochemistry, ×400). f Moderate DNs and sparse NCIs (inset) in the putamen (ubiquitin immunohistochemistry, ×400, inset ×600)
Fig. 6
Fig. 6
Inclusions in the motor nuclei of the brain stem and spinal cord in FTLD with TARDBP 3′-UTR variant. a A Bunina body (arrow) in a cervical anterior horn neuron (H&E, ×600) and b a delicate single neuronal cytoplasmic skein (b TDP-43 immunohistochemistry, ×600). c Lewy body-like inclusions in neurons of the hypoglossal nucleus (TDP-43 immunohistochemistry, ×400). d Lewy body-like inclusions in neurons of the substantia nigra (TDP-43 immunohistochemistry, ×400). e A glial inclusion in the cervical cord (TDP-43 immunohistochemistry, ×600)
Fig. 7
Fig. 7
Sparse to moderate numbers of NCIs (arrows) in the dentate gyrus (TDP-43 immunohistochemistry, ×400)
Fig. 8
Fig. 8
C-terminal specific anti-TDP-43 antibodies preferentially label epitopes within neuronal NCIs of FTLD with TARDBP 3′-UTR variant. a, b NCI s in the dentate gyrus of the proband. a C-t-specific and b N-t-specific TDP-43 immunohistochemistry. a The majority of NCIs are C-t-positive. b A few NCIs are only weakly labeled by N-t-specific anti-TDP-43 antibodies. The nuclei are labeled by N-t-specific anti-TDP-43 antibodies, but not by the ‘disease-specific’ anti-C-t antibodies. Some neurons with weak N-t labeling of NCIs have N-t-negative nuclei. (C-t- and N-t-specific TDP-43 immunohistochemistry, ×600). NCIs in the dentate gyrus of the proband's brother show (c) similar C-terminal-specific labeling and (d) only weak N-terminal-specific labeling as in the proband (a, b). There are sparse C-t-positive NCIs, but not N-t-positive NCIs; some nuclei, however, are N-t-negative (C-t- and N-t-specific TDP-43 immunohistochemistry, ×600). Neuronal inclusion in the hypoglossal nuclei of the proband (e) and proband's brother (f). In both (e) and (f), C-t-specific TDP-43 immunohistochemistry is on the left and N-t-specific labeling is on the right. The lower motor neuron NCIs are labeled by both antibodies. In addition, glial cytoplasmic inclusions are labeled with anti-N-t TDP-43, but only very weakly with anti-C-t TDP-43 antibodies (arrows) (C-t-specific and N-t-specific TDP-43 immunohistochemistry; e ×600, f ×400)

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