Beijer Danique, Marte Sheila, Li Jiaxin C, De Ridder Willem, Chen Jessie Z, Tadenev Abigail L D, Miers Kathy E, Deconinck Tine, Macdonell Richard, Marques Wilson, De Jonghe Peter, Pratt Samia L, Meyer-Schuman Rebecca, Züchner Stephan, Antonellis Anthony, Burgess Robert W, Baets Jonathan
Translational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, B-2610, Belgium.
Laboratory of Neuromuscular Pathology, Institute Born-Bunge, University of Antwerp, Wilrijk, B-2610, Belgium.
Brain Commun. 2024 Mar 8;6(2):fcae070. doi: 10.1093/braincomms/fcae070. eCollection 2024.
Pathogenic variants in six aminoacyl-tRNA synthetase (ARS) genes are implicated in neurological disorders, most notably inherited peripheral neuropathies. ARSs are enzymes that charge tRNA molecules with cognate amino acids. Pathogenic variants in asparaginyl-tRNA synthetase () cause a neurological phenotype combining developmental delay, ataxia and demyelinating peripheral neuropathy. has not yet been linked to axonal Charcot-Marie-Tooth disease. Exome sequencing of patients with inherited peripheral neuropathies revealed three previously unreported heterozygous variants in three families. Clinical and electrophysiological details were assessed. We further characterized all three variants in a yeast complementation model and used a knock-in mouse model to study variant p.Ser461Phe. All three variants (p.Met236del, p.Cys342Tyr and p.Ser461Phe) co-segregate with the sensorimotor axonal neuropathy phenotype. Yeast complementation assays show that none of the three NARS1 variants support wild-type yeast growth when tested in isolation (i.e. in the absence of a wild-type copy of NARS1), consistent with a loss-of-function effect. Similarly, the homozygous knock-in mouse model (p.Ser461Phe/Ser472Phe in mouse) also demonstrated loss-of-function characteristics. We present three previously unreported variants segregating with a sensorimotor neuropathy phenotype in three families. Functional studies in yeast and mouse support variant pathogenicity. Thus, is the seventh ARS implicated in dominant axonal Charcot-Marie-Tooth disease, further stressing that all dimeric ARSs should be evaluated for Charcot-Marie-Tooth disease.
六个氨酰 - tRNA合成酶（ARS）基因中的致病性变异与神经系统疾病有关，最显著的是遗传性周围神经病。ARS是将tRNA分子与相应氨基酸结合的酶。天冬酰胺 - tRNA合成酶（）中的致病性变异导致一种结合发育迟缓、共济失调和脱髓鞘性周围神经病的神经学表型。尚未与轴索性夏科 - 马里 - 图斯病相关联。对遗传性周围神经病患者进行外显子组测序，在三个家族中发现了三个先前未报道的杂合变异。评估了临床和电生理细节。我们在酵母互补模型中进一步表征了所有三个变异，并使用敲入小鼠模型研究变异p.Ser461Phe。所有三个变异（p.Met236del、p.Cys342Tyr和p.Ser461Phe）与感觉运动轴索性神经病表型共分离。酵母互补试验表明，当单独测试时（即不存在NARS1的野生型拷贝时），三个NARS1变异均不支持野生型酵母生长，这与功能丧失效应一致。同样，纯合敲入小鼠模型（小鼠中的p.Ser461Phe/Ser472Phe）也表现出功能丧失特征。我们展示了三个先前未报道的变异，它们在三个家族中与感觉运动神经病表型共分离。在酵母和小鼠中的功能研究支持变异的致病性。因此，是第七个与显性轴索性夏科 - 马里 - 图斯病相关的ARS，进一步强调对于夏科 - 马里 - 图斯病应评估所有二聚体ARS。
