Two German kindreds with familial amyotrophic lateral sclerosis due to TARDBP mutations - PubMed (original) (raw)

Two German kindreds with familial amyotrophic lateral sclerosis due to TARDBP mutations

Peter Kühnlein et al. Arch Neurol. 2008 Sep.

Abstract

Background: Abnormal neuronal inclusions composed of the transactivation response DNA-binding protein 43 (TDP-43) are characteristic neuropathologic lesions in sporadic and familial forms of amyotrophic lateral sclerosis (ALS). This makes TARDBP, the gene encoding for TDP-43, a candidate for genetic screening in ALS.

Objectives: To investigate the presence and frequency of TARDBP mutations in ALS.

Design: Genetic analysis.

Setting: Academic research.

Participants: One hundred thirty-four patients with sporadic ALS, 31 patients with familial non-superoxide dismutase 1 gene (non-SOD1) (OMIM 147450) ALS, and 400 healthy control subjects.

Main outcome measures: We identified 2 missense mutations (G348C and the novel N352S) in TARDBP in 2 small kindreds with a hereditary form of ALS with early spinal onset resulting in fatal respiratory insufficiency without clinical relevant bulbar symptoms or signs of cognitive impairment.

Results: The mutations located in the C-terminus of TDP-43 were absent in 400 controls of white race/ethnicity. The novel identified N352S mutation is predicted to increase TDP-43 phosphorylation, while the G348C mutation might interfere with normal TDP-43 function by forming intermolecular disulfide bridges.

Conclusions: Mutations in TARDBP are a rare cause of familial non-SOD1 ALS. The identification of TARDBP mutations provides strong evidence for a direct link between TDP-43 dysfunction and neurodegeneration in ALS.

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Figures

Figure 1

Figure 1

(A) Pedigree diagram of family A with the G348C mutation in TARDBP. (B) Chromatograms of part of exon 6 of the TARDBP gene showing G348C mutation in the index patient. (C) Pedigree diagram of family B with the N352S mutation in TARDBP. (D) Chromatograms of part of exon 6 of the TARDBP gene showing N352S mutation in the index patient. Filled symbols indicate affected individuals, “?” indicates possibly affected subjects. Arrow indicates index patients.

Figure 2

Figure 2

(A) Sequence alignment of amino acids 340-360 of TDP-43 from diverse vertebrate species. Mutation sites are bold. (B) Effects of TARDBP mutation G348C and N352S on protein structure and function predicted using PolyPhen software program and on phosphorylation site prediction using NetPhos 2.0 program. *The lower the score, the more benign the substitution. ** The higher the score, the higher the probability for phosphorylation. Phopshorylation sites for predicted scores are bold.

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