A Recurrent loss-of-function alanyl-tRNA synthetase (AARS ) mutation in patients with charcot-marie-tooth disease type 2N (CMT2N)
✍ Scribed by Heather M. McLaughlin; Reiko Sakaguchi; William Giblin; NIH Intramural Sequencing Center; Thomas E. Wilson; Leslie Biesecker; James R. Lupski; Kevin Talbot; Jeffery M. Vance; Stephan Züchner; Yi-Chung Lee; Marina Kennerson; Ya-Ming Hou; Garth Nicholson; Anthony Antonellis
- Publisher
- John Wiley and Sons
- Year
- 2011
- Tongue
- English
- Weight
- 426 KB
- Volume
- 33
- Category
- Article
- ISSN
- 1059-7794
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✦ Synopsis
Charcot-Marie-Tooth (CMT) disease comprises a heterogeneous group of peripheral neuropathies characterized by muscle weakness and wasting, and impaired sensation in the extremities. Four genes encoding an aminoacyl-tRNA synthetase (ARS) have been implicated in CMT disease. ARSs are ubiquitously expressed, essential enzymes that ligate amino acids to cognate tRNA molecules. Recently, a p.Arg329His variant in the alanyl-tRNA synthetase (AARS) gene was found to segregate with dominant axonal CMT type 2N (CMT2N) in two French families; however, the functional consequence of this mutation has not been determined. To investigate the role of AARS in CMT, we performed a mutation screen of the AARS gene in patients with peripheral neuropathy. Our results showed that p.Arg329His AARS also segregated with CMT disease in a large Australian family. Aminoacylation and yeast viability assays showed that p.Arg329His AARS severely reduces enzyme activity. Genotyping analysis indicated that this mutation arose on three distinct haplotypes, and the results of bisulfite sequencing suggested that methylation-mediated deamina-