Bi‐allelic <i><scp>IARS</scp></i> mutations in a child with intra‐uterine growth retardation, neonatal cholestasis, and mild developmental delay

Orenstein, Naama; Weiss, Karin; Oprescu, Stephanie N.; Shapira, R; Kidron, Dvora; Vanagaite‐Basel, Lina; Antonellis, Anthony; Muenke, Maximilian

doi:10.1111/cge.12930

Cited by 24 publications

(32 citation statements)

References 13 publications

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“… 32 , 52 Autosomal-recessive IARS (encoding isoleucyl-tRNA synthetase) (MIM: 617093 ) deficiency is associated with liver disease, hypotonia, and intellectual disability. 23 , 24 In contrast to our findings with deficiency of cytoplasmic FARSB , compound heterozygous mutations in nuclear-encoded FARS2 (the mitochondrial phenylalanyl-tRNA synthetase) lead to combined oxidative phosphorylation deficiency associated with global developmental delay, refractory seizures, and lactic acidosis. 53 Interestingly, in three individuals (P1, P3, and P5) a mitochondrial disease was suspected clinically.…”

Section: Discussioncontrasting

confidence: 99%

“… 16 Some studies also measured the amount of charged tRNA in participants’ cells or analyzed the mutated genes in yeast complementation assays. 23 , 24 , 25 , 30 , 51 However, it is unclear how well the changes observed in these assays correlate with a significant compromise of cellular translation. The puromycin incorporation assay used here is an effective way to evaluate overall protein synthesis in cultured cells, to test whether a mutation affects the cellular translational machinery and, if not, to point to a disease mechanism due to an orthogonal, non-canonical function of aaRS.…”

Section: Discussionmentioning

confidence: 99%

“…Bi-allelic mutations in genes for lysyl, glycyl, methionyl-, isoleucyl-, glutamyl-, and arginyl-tRNA synthetases have been reported. 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 Phenotypes associated with these mutations are variable and whether they arise from defects in protein synthesis has either not been explored or is controversial. However, mice haploinsufficient for GARS have a 50% decrease in enzymatic activity in vitro and in tissues, but nonetheless have a normal phenotype and lifespan.…”

Section: Introductionmentioning

confidence: 99%

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Bi-allelic Mutations in Phe-tRNA Synthetase Associated with a Multi-system Pulmonary Disease Support Non-translational Function

Beck

et al. 2018

The American Journal of Human Genetics

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The tRNA synthetases catalyze the first step of protein synthesis and have increasingly been studied for their nuclear and extra-cellular ex-translational activities. Human genetic conditions such as Charcot-Marie-Tooth have been attributed to dominant gain-of-function mutations in some tRNA synthetases. Unlike dominantly inherited gain-of-function mutations, recessive loss-of-function mutations can potentially elucidate ex-translational activities. We present here five individuals from four families with a multi-system disease associated with bi-allelic mutations in FARSB that encodes the beta chain of the alpha2beta2 phenylalanine-tRNA synthetase (FARS). Collectively, the mutant alleles encompass a 5′-splice junction non-coding variant (SJV) and six missense variants, one of which is shared by unrelated individuals. The clinical condition is characterized by interstitial lung disease, cerebral aneurysms and brain calcifications, and cirrhosis. For the SJV, we confirmed exon skipping leading to a frameshift associated with noncatalytic activity. While the bi-allelic combination of the SJV with a p.Arg305Gln missense mutation in two individuals led to severe disease, cells from neither the asymptomatic heterozygous carriers nor the compound heterozygous affected individual had any defect in protein synthesis. These results support a disease mechanism independent of tRNA synthetase activities in protein translation and suggest that this FARS activity is essential for normal function in multiple organs.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Bi-allelic Mutations in Phe-tRNA Synthetase Associated with a Multi-system Pulmonary Disease Support Non-translational Function

Beck

et al. 2018

The American Journal of Human Genetics

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“…Solid line indicates dominant mode of inheritance, dashed line indicates recessive mode of inheritance. References: AARS , DARS , HARS , IARS MARS , RARS , S ARS , W ARS , ARS , QARS , GARS , KARS , AARS 2 , CARS 2 , DARS 2 , EARS 2 , FARS 2 , HARS 2 , IARS 2 , LARS 2 , MARS 2 , NARS 2 , PARS 2 , RARS 2 , S ARS 2 , TARS 2 , VARS 2 , WARS 2 , YARS 2 .…”

Section: Mitochondrial Trna Synthetases (Ars2 Genes)mentioning

confidence: 99%

The role of tRNA synthetases in neurological and neuromuscular disorders

2018

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Aminoacyl‐tRNA synthetases (ARSs) are ubiquitously expressed enzymes responsible for charging tRNAs with their cognate amino acids, therefore essential for the first step in protein synthesis. Although the majority of protein synthesis happens in the cytosol, an additional translation apparatus is required to translate the 13 mitochondrial DNA‐encoded proteins important for oxidative phosphorylation. Most ARS genes in these cellular compartments are distinct, but two genes are common, encoding aminoacyl‐tRNA synthetases of glycine (GARS) and lysine (KARS) in both mitochondria and the cytosol. Mutations in the majority of the 37 nuclear‐encoded human ARS genes have been linked to a variety of recessive and dominant tissue‐specific disorders. Current data indicate that impaired enzyme function could explain the pathogenicity, however not all pathogenic ARSs mutations result in deficient catalytic function; thus, the consequences of mutations may arise from other molecular mechanisms. The peripheral nerves are frequently affected, as illustrated by the high number of mutations in cytosolic and bifunctional tRNA synthetases causing Charcot–Marie–Tooth disease (CMT). Here we provide insights on the pathomechanisms of CMT‐causing tRNA synthetases with specific focus on the two bifunctional tRNA synthetases (GARS, KARS).

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“…2 Consistent with this notion, functional studies have revealed that recessive disease-associated ARS mutations cause reduced protein abundance in immunoblot assays, [5][6][7][8][9][10][11][12][13][14][15][16][17] decreased mutant enzyme activity via in vitro kinetic assays, 9,[18][19][20][21][22][23][24][25] and/or diminished ability of the mutated gene to support cellular growth in yeast complementation assays. 12,13,21,22,[26][27][28][29][30][31][32][33] As such, impaired protein translation as a consequence of decreased tRNA charging is the most likely molecular mechanism for ARS-mediated recessive disease. 2 Here, we report on four affected individuals from three unrelated families.…”

mentioning

confidence: 99%

Cysteinyl-tRNA Synthetase Mutations Cause a Multi-System, Recessive Disease That Includes Microcephaly, Developmental Delay, and Brittle Hair and Nails

Kuo

Theil

Kievit

et al. 2019

The American Journal of Human Genetics

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Aminoacyl-tRNA synthetases (ARSs) are essential enzymes responsible for charging tRNA molecules with cognate amino acids. Consistent with the essential function and ubiquitous expression of ARSs, mutations in 32 of the 37 ARS-encoding loci cause severe, early-onset recessive phenotypes. Previous genetic and functional data suggest a loss-of-function mechanism; however, our understanding of the allelic and locus heterogeneity of ARS-related disease is incomplete. Cysteinyl-tRNA synthetase (CARS) encodes the enzyme that charges tRNA Cys with cysteine in the cytoplasm. To date, CARS variants have not been implicated in any human disease phenotype. Here, we report on four subjects from three families with complex syndromes that include microcephaly, developmental delay, and brittle hair and nails. Each affected person carries bi-allelic CARS variants: one individual is compound heterozygous for c.1138C>T (p.Gln380*) and c.1022G>A (p.Arg341His), two related individuals are compound heterozygous for c.1076C>T (p.Ser359Leu) and c.1199T>A (p.Leu400Gln), and one individual is homozygous for c.2061dup (p.Ser688Glnfs*2). Measurement of protein abundance, yeast complementation assays, and assessments of tRNA charging indicate that each CARS variant causes a loss-of-function effect. Compared to subjects with previously reported ARS-related diseases, individuals with bi-allelic CARS variants are unique in presenting with a brittle-hair-and-nail phenotype, which most likely reflects the high cysteine content in human keratins. In sum, our efforts implicate CARS variants in human inherited disease, expand the locus and clinical heterogeneity of ARS-related clinical phenotypes, and further support impaired tRNA charging as the primary mechanism of recessive ARS-related disease.

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Bi‐allelic IARS mutations in a child with intra‐uterine growth retardation, neonatal cholestasis, and mild developmental delay

Cited by 24 publications

References 13 publications

Bi-allelic Mutations in Phe-tRNA Synthetase Associated with a Multi-system Pulmonary Disease Support Non-translational Function

Bi-allelic Mutations in Phe-tRNA Synthetase Associated with a Multi-system Pulmonary Disease Support Non-translational Function

The role of tRNA synthetases in neurological and neuromuscular disorders

Cysteinyl-tRNA Synthetase Mutations Cause a Multi-System, Recessive Disease That Includes Microcephaly, Developmental Delay, and Brittle Hair and Nails

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