Dataset Information

A missense, loss-of-function YARS1 variant in a patient with proximal-predominant motor neuropathy.

ABSTRACT: Aminoacyl-tRNA synthetases (ARSs) are essential enzymes with a critical role in protein synthesis: charging tRNA molecules with cognate amino acids. Heterozygosity for variants in five genes (AARS1, GARS1, HARS1, WARS1, and YARS1) encoding cytoplasmic, dimeric ARSs have been associated with autosomal dominant neurological phenotypes, including axonal Charcot-Marie-Tooth disease (CMT). Missense variants in the catalytic domain of YARS1 were previously linked to dominant intermediate CMT type C (DI-CMTC). Here, we report a patient with a missense variant of unknown significance predicted to modify residue 308 in the anticodon binding domain of YARS1 (p.Asp308Tyr). Interestingly, p.Asp308Tyr is associated with proximal-predominant motor neuropathy, which has not been reported in patients with pathogenic YARS1 variants. We demonstrate that this allele causes a loss-of-function effect in yeast complementation assays when modeled in YARS1 and the yeast ortholog TYS1; structural modeling of this variant further supports a loss-of-function effect. Taken together, this study raises the possibility that certain YARS1 variants cause proximal-prominent motor neuropathy and indicates that patients with this phenotype should be screened for genetic lesions in YARS1.

SUBMITTER: Forrest ME

PROVIDER: S-EPMC9808560 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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A missense, loss-of-function YARS1 variant in a patient with proximal-predominant motor neuropathy.

Forrest Megan E ME Meyer Alayne P AP Laureano Figueroa Stephanie M SM Antonellis Anthony A

Cold Spring Harbor molecular case studies 20221228 7

Aminoacyl-tRNA synthetases (ARSs) are essential enzymes with a critical role in protein synthesis: charging tRNA molecules with cognate amino acids. Heterozygosity for variants in five genes (AARS1, GARS1, HARS1, WARS1, and YARS1) encoding cytoplasmic, dimeric ARSs have been associated with autosomal dominant neurological phenotypes, including axonal Charcot-Marie-Tooth disease (CMT). Missense variants in the catalytic domain of YARS1 were previously lin ...[more]

PMID: 36307205

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Project description:Background and objectivesCDKL5 deficiency disorder (CDD) is a neurodevelopmental encephalopathy characterized by early-onset epilepsy and impaired psychomotor development. Variations in the X-linked CDKL5 gene coding for a kinase cause CDD. Molecular genetics has proved that almost all pathogenic missense substitutions localize in the N-terminal catalytic domain, therefore underlining the importance for brain development and functioning of the kinase activity. CDKL5 also features a long C-terminal domain that acts as negative regulator of the enzymatic activity and modulates its subcellular distribution. CDD is generally attributed to loss-of-function variations, whereas the clinical consequences of increased CDKL5 activity remain uncertain. We have identified a female patient characterized by mild epilepsy and neurologic symptoms, harboring a novel c.2873C>G nucleotide substitution, leading to the missense variant p.(Thr958Arg). To increase our comprehension of genetic variants in CDKL5-associated neurologic disorders, we have characterized the molecular consequences of the identified substitution.MethodsMRI and video EEG telemetry were used to describe brain activity and capture seizure. The Bayley III test was used to evaluate the patient development. Reverse transcriptase PCR was used to analyze whether the identified nucleotide variant affects messenger RNA stability and/or splicing. The X chromosome inactivation pattern was analyzed determining the DNA methylation status of the androgen receptor (AR) gene and by sequencing of expressed alleles. Western blotting was used to investigate whether the novel Thr958Arg substitution affects the stability and/or enzymatic activity of CDKL5. Immunofluorescence was used to define whether CDKL5 subcellular distribution is affected by the Thr958Arg substitution.ResultsOur data suggested that the proband tends toward a skewed X chromosome inactivation pattern in favor of the novel variant. The molecular investigation revealed that the p.(Thr958Arg) substitution leads to a significant increase in the autophosphorylation of both the TEY motif and residue Tyr171 of CDKL5, as well as in the phosphorylation of the target protein MAP1S, indicating an hyperactivation of CDKL5. This occurs without evidently affecting the kinase subcellular distribution.DiscussionOur data provide a strong indication that the c.2873C>G nucleotide substitution represents an hypermorphic pathogenic variation of CDKL5, therefore highlighting the importance of a tight control of CDKL5 activity in the brain.

Dataset Information

A missense, loss-of-function YARS1 variant in a patient with proximal-predominant motor neuropathy.

Publications

A missense, loss-of-function <i>YARS1</i> variant in a patient with proximal-predominant motor neuropathy.

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