CMT disease-associated mutant tRNA synthetases linked to altered dimer interface

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PNAS | July 3, 2007 | vol. 104 | no. 27 | 11239-11244

Charcot–Marie–Tooth disease-associated mutant tRNA synthetases

linked to altered dimer interface and neurite distribution defect

A. Nangle, Wei Zhang, Wei Xie, Xiang-Lei Yang*, and

Schimmel*

The Skaggs Institute for Chemical Biology and the Department of

Molecular Biology, The Scripps Research Institute, BCC-379, 10550

North Torrey Pines Road, La Jolla, CA 92037

Charcot–Marie–Tooth (CMT) diseases are the most common heritable

peripheral neuropathy. At least 10 different mutant alleles of GARS

(the gene for glycyl-tRNA synthetase) have been reported to cause a

dominant axonal form of CMT (type 2D). A unifying connection between

these mutations and CMT has been unclear. Here, mapping mutations

onto the recently determined crystal structure of human GlyRS showed

them within a band encompassing both sides of the dimer interface,

with two CMT-causing mutations being at sites that are complementary

partners of a " kissing " contact across the dimer interface. The CMT

phenotype is shown here to not correlate with aminoacylation

activity. However, most mutations affect dimer formation (to enhance

or weaken). Seven CMT-causing variants and the wild-type protein

were expressed in transfected neuroblastoma cells that sprout

primitive neurites. Wild-type GlyRS distributed into the nascent

neurites and was associated with normal neurite sprouting. In

contrast, all mutant proteins were distribution-defective. Thus, CMT-

causing mutations of GlyRS share a common defect in localization.

This defect may be connected in some way to a change in the surfaces

at the dimer interface.