Disrupted function and axonal distribution of mutant tyrosyl-tRNA synthetase in dominant intermediate Charcot-Marie-Tooth neuropathy.
Charcot-Marie-Tooth (CMT) neuropathies are common disorders of the peripheral nervous system caused by demyelination or axonal degeneration, or a combination of both features. We previously assigned the locus for autosomal dominant intermediate CMT neuropathy type C (DI-CMTC) to chromosome 1p34-p35. Here we identify two heterozygous missense mutations (G41R and E196K) and one de novo deletion (153-156delVKQV) in tyrosyl-tRNA synthetase (YARS) in three unrelated families affected with DI-CMTC. Biochemical experiments and genetic complementation in yeast show partial loss of aminoacylation activity of the mutant proteins, and mutations in YARS, or in its yeast ortholog TYS1, reduce yeast growth. YARS localizes to axonal termini in differentiating primary motor neuron and neuroblastoma cultures. This specific distribution is significantly reduced in cells expressing mutant YARS proteins. YARS is the second aminoacyl-tRNA synthetase found to be involved in CMT, thereby linking protein-synthesizing complexes with neurodegeneration.
Jordanova
Albena
A
Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology, University of Antwerp, Universiteitsplein 1, 2610 Antwerpen, Belgium.
Irobi
Joy
J
Thomas
Florian P
FP
Van Dijck
Patrick
P
Meerschaert
Kris
K
Dewil
Maarten
M
Dierick
Ines
I
Jacobs
An
A
De Vriendt
Els
E
Guergueltcheva
Velina
V
Rao
Chitharanjan V
CV
Tournev
Ivailo
I
Gondim
Francisco A A
FA
D'Hooghe
Marc
M
Van Gerwen
Veerle
V
Callaerts
Patrick
P
Van Den Bosch
Ludo
L
Timmermans
Jean-Pièrre
JP
Robberecht
Wim
W
Gettemans
Jan
J
Thevelein
Johan M
JM
De Jonghe
Peter
P
Kremensky
Ivo
I
Timmerman
Vincent
V
D000595:Amino Acid Sequence; D000818:Animals; D001369:Axons / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D001681:Biological Assay; D019556:COS Cells; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002607:Charcot-Marie-Tooth Disease / Q000201:enzymology* / Q000235:genetics* / Q000378:metabolism; D002522:Chlorocebus aethiops; D005799:Genes, Dominant / Q000235:genetics*; D005816:Genetic Complementation Test; D006579:Heterozygote; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D021381:Protein Transport; D011994:Recombinant Proteins; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000254:growth & development; D016415:Sequence Alignment; D014448:Tyrosine-tRNA Ligase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*
D011994:Recombinant Proteins; D014448:Tyrosine-tRNA Ligase