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Normal Function
The GARS1 gene provides instructions for making an enzyme called glycine—tRNA ligase. This enzyme is found in all cell types and plays an important role in the production of proteins. During protein production, protein building blocks (amino acids) are connected together in a specific order, creating a chain of amino acids. Glycine—tRNA ligase helps add the amino acid glycine at the proper place in a protein's chain of amino acids.
Health Conditions Related to Genetic Changes
Distal hereditary motor neuropathy, type V
Several GARS1 gene variants (also called mutations) have been found to cause distal hereditary motor neuropathy, type V. This condition affects nerve cells (neurons) in the spinal cord. Specifically, it affects motor neurons, which are specialized cells that control muscle movement. Affected individuals develop muscle weakness that impairs the movement of the hands and feet. The GARS1 gene variants that cause distal hereditary motor neuropathy, type V lead to changes in single amino acids used to make glycine—tRNA ligase. While these variants reduce the activity of glycine—tRNA ligase, it is unclear how this change causes the disorder. A reduction in glycine—tRNA ligase activity may impair the transmission of nerve impulses and lead to a loss of communication between motor neurons and muscles in the hands and feet.
More About This Health ConditionCharcot-Marie-Tooth disease
MedlinePlus Genetics provides information about Charcot-Marie-Tooth disease
More About This Health ConditionOther disorders
GARS1 gene variants have been found to cause a condition called GARS1 infantile-onset spinal muscular atrophy (also known as infantile spinal muscular atrophy, James type). Affected individuals often show weak muscle tone (hypotonia) in early infancy. Muscle weakness, primarily in the lower arms and legs, impairs children’s ability to walk and grasp objects with their hands. Over time, worsening muscle weakness can cause problems with eating, speaking, and breathing in people with GARS1 infantile-onset spinal muscular atrophy.
Similar to distal hereditary motor neuropathy, type V, the variants that cause GARS1 infantile-onset spinal muscular atrophy change single amino acids in glycine—tRNA ligase. It is unclear how these changes cause the condition, though a reduction in glycine—tRNA ligase activity in people with GARS1 infantile-onset spinal muscular atrophy may impair motor neuron function in a similar way to people with distal hereditary motor neuropathy, type V. This may cause the severe muscle weakness seen in people with GARS1 infantile-onset spinal muscular atrophy.
Other Names for This Gene
- CMT2D
- DSMAV
- GARS
- glycine tRNA ligase
- GlyRS
- SMAD1
- SYG_HUMAN
Additional Information & Resources
Tests Listed in the Genetic Testing Registry
Scientific Articles on PubMed
Catalog of Genes and Diseases from OMIM
References
- Antonellis A, Ellsworth RE, Sambuughin N, Puls I, Abel A, Lee-Lin SQ, Jordanova A, Kremensky I, Christodoulou K, Middleton LT, Sivakumar K, Ionasescu V, Funalot B, Vance JM, Goldfarb LG, Fischbeck KH, Green ED. Glycyl tRNA synthetase mutations in Charcot-Marie-Tooth disease type 2D and distal spinal muscular atrophy type V. Am J Hum Genet. 2003 May;72(5):1293-9. doi: 10.1086/375039. Epub 2003 Apr 10. Citation on PubMed or Free article on PubMed Central
- Antonellis A, Lee-Lin SQ, Wasterlain A, Leo P, Quezado M, Goldfarb LG, Myung K, Burgess S, Fischbeck KH, Green ED. Functional analyses of glycyl-tRNA synthetase mutations suggest a key role for tRNA-charging enzymes in peripheral axons. J Neurosci. 2006 Oct 11;26(41):10397-406. doi: 10.1523/JNEUROSCI.1671-06.2006. Citation on PubMed
- Griffin LB, Sakaguchi R, McGuigan D, Gonzalez MA, Searby C, Zuchner S, Hou YM, Antonellis A. Impaired function is a common feature of neuropathy-associated glycyl-tRNA synthetase mutations. Hum Mutat. 2014 Nov;35(11):1363-71. doi: 10.1002/humu.22681. Citation on PubMed or Free article on PubMed Central
- James PA, Cader MZ, Muntoni F, Childs AM, Crow YJ, Talbot K. Severe childhood SMA and axonal CMT due to anticodon binding domain mutations in the GARS gene. Neurology. 2006 Nov 14;67(9):1710-2. doi: 10.1212/01.wnl.0000242619.52335.bc. Citation on PubMed
- Nangle LA, Zhang W, Xie W, Yang XL, Schimmel P. Charcot-Marie-Tooth disease-associated mutant tRNA synthetases linked to altered dimer interface and neurite distribution defect. Proc Natl Acad Sci U S A. 2007 Jul 3;104(27):11239-44. doi: 10.1073/pnas.0705055104. Epub 2007 Jun 26. Citation on PubMed or Free article on PubMed Central
- Sivakumar K, Kyriakides T, Puls I, Nicholson GA, Funalot B, Antonellis A, Sambuughin N, Christodoulou K, Beggs JL, Zamba-Papanicolaou E, Ionasescu V, Dalakas MC, Green ED, Fischbeck KH, Goldfarb LG. Phenotypic spectrum of disorders associated with glycyl-tRNA synthetase mutations. Brain. 2005 Oct;128(Pt 10):2304-14. doi: 10.1093/brain/awh590. Epub 2005 Jul 13. Citation on PubMed
- Sleigh JN, Dawes JM, West SJ, Wei N, Spaulding EL, Gomez-Martin A, Zhang Q, Burgess RW, Cader MZ, Talbot K, Yang XL, Bennett DL, Schiavo G. Trk receptor signaling and sensory neuron fate are perturbed in human neuropathy caused by Gars mutations. Proc Natl Acad Sci U S A. 2017 Apr 18;114(16):E3324-E3333. doi: 10.1073/pnas.1614557114. Epub 2017 Mar 28. Citation on PubMed or Free article on PubMed Central
- Xie W, Nangle LA, Zhang W, Schimmel P, Yang XL. Long-range structural effects of a Charcot-Marie-Tooth disease-causing mutation in human glycyl-tRNA synthetase. Proc Natl Acad Sci U S A. 2007 Jun 12;104(24):9976-81. doi: 10.1073/pnas.0703908104. Epub 2007 Jun 1. Citation on PubMed or Free article on PubMed Central
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