GARS‐related disease in infantile spinal muscular atrophy: Implications for diagnosis and treatment

Abstract

The majority of patients with spinal muscular atrophy (SMA) identified to date harbor a biallelic exonic deletion of SMN1. However, there have been reports of SMA-like disorders that are independent of SMN1, including those due to pathogenic variants in the glycyl-tRNA synthetase gene (GARS1). We report three unrelated patients with de novo variants in GARS1 that are associated with infantile-onset SMA (iSMA).Patients were ascertained during inpatient hospital evaluations for complications of neuropathy. Evaluations were completed as indicated for clinical care and management and informed consent for publication was obtained. One newly identified, disease-associated GARS1 variant, identified in two out of three patients, was analyzed by functional studies in yeast complementation assays. Genomic analyses by exome and/or gene panel and SMN1 copy number analysis of three patients identified two previously undescribed de novo missense variants in GARS1 and excluded Rebecca Markovitz and Rajarshi Ghosh as co-first authors.

Infantile‐onset CMT2D/dSMA‐V in a Chinese family with parental germline mosaicism for a novel mutation in the GARS1 gene

“…In 2012, Eskuri et al reported monozygotic twin girls from the United State with a severe, infantileonset CMT2D/dSMA-V (Eskuri et al, 2012), similar to the patient reported by James et al (2006), and a mutation (G652A) within the anticodon-binding domain of GARS1 was found by direct Sanger sequencing (Eskuri et al, 2012). Afterward, eight individuals with infantile-onset CMT/ dSMA-V were reported from Taiwan, Korea, and the USA, and the genetic tests were performed by next-generation sequencing (NGS), including panel, ES, or trio-ES (Chae et al, 2015;Chung et al, 2018;Eskuri et al, 2012;James et al, 2006;Liao et al, 2015;Markovitz et al, 2020). All these mutations identified in these patients were de novo, except three siblings from a Nigerian descent family in the USA, whose variant (c.815T>G, p.L272R) was inherited from their healthy mother with low-level (10%-20%) mosaicism (Chung et al, 2018).…”

“…To date, a total of 12 patients have been reported to present clinical symptoms of CMT2D/dSMA-V at infancy or early childhood, caused by seven missense mutations, c.598G>T (p.D200Y), c.815T>G (p.L272R), c.998A>G (p.E333G), c.1001T>A (p.L334N), c.2313G>C (p.G598A), c.1954G>C (p.G652R), and c.1955G>C (p.G652A), respectively (Chae et al, 2015;Chung et al, 2018;Eskuri et al, 2012;James et al, 2006;Liao et al, 2015;Markovitz et al, 2020). As shown in Table 1 and Figure 1f, among these variants, only the variant (p.L272R) lies on catalytic domain, three mutations, p.G652R, p.G652A, and p.G598A on anticodon-binding domains, and the other three (p.D200Y, p.E333G, and p.L334N) on dimer interface regions (Figure 1f).…”

“…CMT2D/dSMA-V typically presents with progressive muscle weakness and atrophy with adolescent or early adult onset (Antonellis et al, 2003); however, a few infantile or early childhood onset cases have been reported (Chae et al, 2015;Chung et al, 2018;Eskuri et al, 2012;James et al, 2006;Liao et al, 2015;Markovitz et al, 2020). Here we report, for the first time, a Chinese family with infantile onset of CMT2D/dSMA-V caused by GARS1 mutation (c.997G>C; NM_002047) probably inherited from mosaic parental germline mutation.…”

Yeast as a Tool to Understand the Significance of Human Disease-Associated Gene Variants

“…This is the case of aminoacyl-tRNA transferases. Mutations in the gene methionyl-tRNA synthetase ( MARS1 ) identified in Charcot-Marie-Tooth disorder type 2U (CMT2U); in glycyl-tRNA synthetase 1 ( GARS1 ) associated with CMT (CMT2D) and with Spinal muscular atrophy; and infantile, James type (SMAJI), and valyl-tRNA synthetase ( VARS1 ), associated with developmental encephalopathy with microcephaly have been successfully studied in yeast [ 46 , 47 , 48 ]. In these studies, gene variants are not retrieved from databases but identified in patients and their families because they are so rare that they have been never reported elsewhere.…”

Mitochondrial Aminoacyl-tRNA Synthetase and Disease: The Yeast Contribution for Functional Analysis of Novel Variants

“…Moreover, it is known that a form of GARS , in which both MTS and WHEP-TRS domains are truncated (MTSΔWHEPΔ), is able to complement the lethality due to the deletion of GRS1 [ 80 , 81 ]. This heterologous complementation approach allowed to demonstrate that I334N and G327R GARS variants do not support the growth of yeast, indicating a severe impairment of protein function [ 26 , 27 ].…”