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Review
. 2023 Mar 29;14(4):822.
doi: 10.3390/genes14040822.

The Expanding Phenotypical Spectrum of WARS2-Related Disorder: Four Novel Cases with a Common Recurrent Variant

Martje G Pauly  1   2   3 , G Christoph Korenke  4 , Sokhna Haissatou Diaw  1 , Anne Grözinger  1 , Ana Cazurro-Gutiérrez  5 , Belén Pérez-Dueñas  5   6 , Victoria González  7 , Alfons Macaya  5 , Ana Teresa Serrano Antón  8 , Borut Peterlin  9 , Ivana Babić Božović  9 , Aleš Maver  9 , Alexander Münchau  2 , Katja Lohmann  1
Affiliations
Review

The Expanding Phenotypical Spectrum of WARS2-Related Disorder: Four Novel Cases with a Common Recurrent Variant

Martje G Pauly et al. Genes (Basel). .

Abstract

Biallelic variants in the mitochondrial form of the tryptophanyl-tRNA synthetases (WARS2) can cause a neurodevelopmental disorder with movement disorders including early-onset tremor-parkinsonism syndrome. Here, we describe four new patients, who all presented at a young age with a tremor-parkinsonism syndrome and responded well to levodopa. All patients carry the same recurrent, hypomorphic missense variant (NM_015836.4: c.37T>G; p.Trp13Gly) either together with a previously described truncating variant (NM_015836.4: c.797Cdel; p.Pro266ArgfsTer10), a novel truncating variant (NM_015836.4: c.346C>T; p.Gln116Ter), a novel canonical splice site variant (NM_015836.4: c.349-1G>A), or a novel missense variant (NM_015836.4: c.475A>C, p.Thr159Pro). We investigated the mitochondrial function in patients and found increased levels of mitochondrially encoded cytochrome C Oxidase II as part of the mitochondrial respiratory chain as well as decreased mitochondrial integrity and branching. Finally, we conducted a literature review and here summarize the broad phenotypical spectrum of reported WARS2-related disorders. In conclusion, WARS2-related disorders are diagnostically challenging diseases due to the broad phenotypic spectrum and the disease relevance of a relatively common missense change that is often filtered out in a diagnostic setting since it occurs in ~0.5% of the general European population.

Keywords: WARS2; levodopa; parkinsonism; tremor.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Figures

Figure 1
Figure 1
Pedigree of the family of Patient 1 (A), Patient 2 (B), Patient 3 (C), and Patient 4 (D). WT: wildtype, n.t.: not tested; square: male, circle: female, white: unaffected, black: affected, striped: isolated tremor.
Figure 2
Figure 2
cDNA sequencing of P3 (A) and M3 ((B); does not carry the c.349-1G>A variant) with skipping of exon 3 and 4 in P3 and skipping of exon 4 only in M3 (alternative transcript, NM_001378231.1).
Figure 3
Figure 3
Representative pictures of immunostaining of cultured fibroblasts with GRP75 of a control (A,D), P1 (B,E), and P2 (C,F) before (A–C) and after paraquat treatment (D–F).
Figure 4
Figure 4
Analysis of the mitochondrially encoded Cytochrome C Oxidase II protein. (A) Representative Western blot for three controls (C1–C3), two biallelic patients (P1, P2), and two heterozygous unaffected relatives (M1, F1) showing protein levels of MT-CO2, which is increased in the patients and in M1 when compared to the controls. Beta-actin was stained as a control for equal loading. (B) Quantification of the signals from three Western blots was performed by analyzing the intensity and volume of the bands using Image Lab 6.1 (Bio-Rad). Ratio of MT-CO2 and β-actin was calculated first, followed by the mean value of all controls, which was standardized as 1. Mean values of patients (P1 and P2) and relatives (M1 and F1) are given as ratio to controls. Error bars: standard deviation. Light gray: wild type; dark gray: heterozygous carriers (parents); black: biallelic carriers (patients).
See this image and copyright information in PMC

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