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Inhibition of TFG function causes hereditary axon degeneration by impairing endoplasmic reticulum structure.


ABSTRACT: Hereditary spastic paraplegias are a clinically and genetically heterogeneous group of gait disorders. Their pathological hallmark is a length-dependent distal axonopathy of nerve fibers in the corticospinal tract. Involvement of other neurons can cause additional neurological symptoms, which define a diverse set of complex hereditary spastic paraplegias. We present two siblings who have the unusual combination of early-onset spastic paraplegia, optic atrophy, and neuropathy. Genome-wide SNP-typing, linkage analysis, and exome sequencing revealed a homozygous c.316C>T (p.R106C) variant in the Trk-fused gene (TFG) as the only plausible mutation. Biochemical characterization of the mutant protein demonstrated a defect in its ability to self-assemble into an oligomeric complex, which is critical for normal TFG function. In cell lines, TFG inhibition slows protein secretion from the endoplasmic reticulum (ER) and alters ER morphology, disrupting organization of peripheral ER tubules and causing collapse of the ER network onto the underlying microtubule cytoskeleton. The present study provides a unique link between altered ER architecture and neurodegeneration.

SUBMITTER: Beetz C 

PROVIDER: S-EPMC3612678 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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Inhibition of TFG function causes hereditary axon degeneration by impairing endoplasmic reticulum structure.

Beetz Christian C   Johnson Adam A   Schuh Amber L AL   Thakur Seema S   Varga Rita-Eva RE   Fothergill Thomas T   Hertel Nicole N   Bomba-Warczak Ewa E   Thiele Holger H   Nürnberg Gudrun G   Altmüller Janine J   Saxena Renu R   Chapman Edwin R ER   Dent Erik W EW   Nürnberg Peter P   Audhya Anjon A  

Proceedings of the National Academy of Sciences of the United States of America 20130311 13


Hereditary spastic paraplegias are a clinically and genetically heterogeneous group of gait disorders. Their pathological hallmark is a length-dependent distal axonopathy of nerve fibers in the corticospinal tract. Involvement of other neurons can cause additional neurological symptoms, which define a diverse set of complex hereditary spastic paraplegias. We present two siblings who have the unusual combination of early-onset spastic paraplegia, optic atrophy, and neuropathy. Genome-wide SNP-typ  ...[more]

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