Faculty Opinions recommendation of Compound heterozygosity for loss-of-function lysyl-tRNA synthetase mutations in a patient with peripheral neuropathy.

Abstract α-Synuclein misfolding and aggregation plays a major role in the pathogenesis of Parkinson’s disease. Although loss of function mutations in the ubiquitin ligase, parkin, cause autosomal recessive Parkinson’s disease, there is evidence that parkin is inactivated in sporadic Parkinson’s disease. Whether parkin inactivation is a driver of neurodegeneration in sporadic Parkinson’s disease or a mere spectator is unknown. Here we show that parkin in inactivated through c-Abelson kinase phosphorylation of parkin in three α-synuclein-induced models of neurodegeneration. This results in the accumulation of parkin interacting substrate protein (zinc finger protein 746) and aminoacyl tRNA synthetase complex interacting multifunctional protein 2 with increased parkin interacting substrate protein levels playing a critical role in α-synuclein-induced neurodegeneration, since knockout of parkin interacting substrate protein attenuates the degenerative process. Thus, accumulation of parkin interacting substrate protein links parkin inactivation and α-synuclein in a common pathogenic neurodegenerative pathway relevant to both sporadic and familial forms Parkinson’s disease. Thus, suppression of parkin interacting substrate protein could be a potential therapeutic strategy to halt the progression of Parkinson’s disease and related α-synucleinopathies.

Download Full-text

T118M Variant of PMP22 Gene Presents with Painful Peripheral Neuropathy and Varying Charcot-Marie-Tooth Features: A Case Series and Review of the Literature

Case Reports in Genetics ◽

10.1155/2018/2618071 ◽

2018 ◽

Vol 2018 ◽

pp. 1-7 ◽

Cited By ~ 2

Author(s):

Kwo Wei David Ho ◽

Nivedita U. Jerath

Keyword(s):

Peripheral Neuropathy ◽

Autosomal Recessive ◽

Clinical Effect ◽

Case Series ◽

Pmp22 Gene ◽

Loss Of Function ◽

Review Of The Literature ◽

Partial Loss ◽

Charcot Marie Tooth ◽

Electrophysiological Studies

The clinical effect of T118M variant of the PMP22 gene has been controversial. Several studies have suggested that it may be autosomal recessive, partial loss of function, or a benign variant. Here we report three cases in further support that the T118M variant of the PMP22 gene is a partial loss of function variant. These three unrelated cases were heterozygotes with the T118M variant of the PMP22 gene. All three cases presented with painful peripheral neuropathy and varying degrees of Charcot-Marie-Tooth exam features. Electrophysiological studies revealed polyneuropathy with axonal and demyelinating features in one case, but there were minimal electrophysiological changes in the other two cases. We propose that the T118M variant can cause painful peripheral neuropathy, which may be an underrecognized feature of this variant.

Download Full-text

Rare recessive loss-of-function methionyl-tRNA synthetase mutations presenting as a multi-organ phenotype

BMC Medical Genetics ◽

10.1186/1471-2350-14-106 ◽

2013 ◽

Vol 14 (1) ◽

Cited By ~ 32

Author(s):

Eline van Meel ◽

Daniel J Wegner ◽

Paul Cliften ◽

Marcia C Willing ◽

Frances V White ◽

...

Keyword(s):

Trna Synthetase ◽

Loss Of Function ◽

Methionyl Trna Synthetase

Download Full-text

Rice TSV2 Encoding Threonyl-tRNA Synthetase is Needed for Early Chloroplast Development and Seedling Growth under Cold Stress

G3 Genes|Genome|Genetics ◽

10.1093/g3journal/jkab196 ◽

2021 ◽

Author(s):

Dongzhi Lin ◽

Wenhao Zhou ◽

Yulu Wang ◽

Jia Sun ◽

Xiaobiao Pan ◽

...

Keyword(s):

Cold Stress ◽

Chloroplast Development ◽

Chlorophyll Biosynthesis ◽

Trna Synthetase ◽

Loss Of Function ◽

Specific Expression ◽

Trna Synthetases ◽

Leaf Stage ◽

Virescent Mutant ◽

Albino Phenotype

Abstract Threonyl-tRNA synthetase (ThrRS), one of aminoacyl-tRNA synthetases (AARSs), plays a crucial role in protein synthesis. However, the AARS functions on rice chloroplast development and growth were not fully appraised. In this study, a thermo-sensitive virescent mutant tsv2, which showed albino phenotype and lethal after the 4-leaf stage at 20 °C but recovered to normal when the temperatures rose, was identified and characterized. Map-based cloning and complementation tests showed that TSV2 encoded a chloroplast-located ThrRS protein in rice. The Lys-to-Arg mutation in the anticodon-binding domain hampered chloroplast development under cold stress, while the loss-of-function of the ThrRS core domain in TSV2 fatally led to seedling death regardless of growing temperatures. In addition, TSV2 had a specific expression in early leaves. Its disruption obviously resulted in down-regulation of certain genes associated with chlorophyll biosynthesis, photosynthesis and chloroplast development at cold conditions. Our observations revealed that rice nuclear-encoded TSV2 plays an important role in chloroplast development at the early leaf stage under cold stress.

Download Full-text