Aminoacyl-tRNA synthetase deficiencies in search of common themes

Fuchs, Sabine A.; Schene, Imre F.; Kok, Gautam; Jansen, Jurriaan M.; Nikkels, Peter G. J.; Gassen, Koen van; Terheggen-Lagro, Suzanne W. J.; Crabben, Saskia N. van der; Hoeks, Sanne E.; Niers, Laetitia E. M.; Wolf, Nicole I.; Vries, Maaike C. de; Koolen, David A.; Houwen, Roderick H. J.; Mulder, Margot F.; Hasselt, Peter M. van

doi:10.1038/s41436-018-0048-y

Cited by 90 publications

(118 citation statements)

References 63 publications

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“…liver, lung, brain and muscle are particularly affected. 4 However, because null variants in tRNA synthetase genes are presumably lethal, 2,11,12 at least one of the variants in our patient is likely to have a residual activity necessary for survival. Notably, none of the reported patients with the FARSB disease had biallelic null loss-of-function variants.…”

Section: Discussionmentioning

confidence: 79%

“…FARSA and FARSB dimers assemble to form PheRS complex. Similar to other synthetases, the clinical picture of PheRs dysfunction stems from unmet demand for proteins in various tissues due to translation deficits . This mechanism is evidenced by the location of pathogenic variants within anticodon or acceptor stem regions of the respective genes and is directly consistent with intrauterine growth restriction and failure to thrive.…”

Section: Discussionmentioning

confidence: 81%

“…High‐protein demand tissues, i.e. liver, lung, brain and muscle are particularly affected . However, because null variants in tRNA synthetase genes are presumably lethal, at least one of the variants in our patient is likely to have a residual activity necessary for survival.…”

Section: Discussionmentioning

confidence: 81%

“…The phenotype of aaRS disorders is variable but often includes intrauterine growth retardation and postnatal growth restriction. Notably, MARS , YARS and FARSB biallelic pathogenic variants have been consistently associated with interstitial lung disease (ILD) …”

Section: Introductionmentioning

confidence: 99%

“…Notably, MARS, YARS and FARSB biallelic pathogenic variants have been consistently associated with interstitial lung disease (ILD). [3][4][5][6][7] Phenylalanyl-tRNA synthetase (PheRs), a cytoplasmic aaRS, is a tetramer formed by two FARSA and two FARSB subunits. 8 Recently, biallelic FARSB mutations were found to cause a multisystem neurodevelopmental disorder of growth restriction, brain calcifications and ILD (Rajab ILD with brain calcifications, MIM#613658).…”

Section: Introductionmentioning

confidence: 99%

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FARSA mutations mimic phenylalanyl‐tRNA synthetase deficiency caused by FARSB defects

et al. 2019

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Pathogenic variants in genes encoding aminoacyl‐tRNA synthetases cause numerous disorders characterized by involvement of neurons, muscles, lungs and liver. Recently, biallelic FARSB defects have been shown to cause severe growth restriction with combined brain, liver and lung involvement (Rajab interstitial lung disease [ILD] with brain calcifications). Herein, for the first time, we present a patient with similar condition associated with biallelic mutations in FARSA (NM_004461.3: c.766T>C:p.Phe256Leu and c.1230C>A:p.Asn410Lys). Both detected FARSA variants are ultrarare and predicted to be damaging by in silico programs. Furthermore, they are both located in the active site of phenylalanyl‐tRNA synthetase (PheRS) with Asn410Lys directly affecting a residue forming the wall of the phenylalanine‐binding pocket. Clinical features shared between our patient and the FARSB syndrome include ILD with cholesterol pneumonitis, growth delay, hypotonia, brain calcifications with cysts and liver dysfunction. Our findings indicate that a disease similar to a syndrome associated with FARSB defects can also be caused by biallelic FARSA mutations. These findings are consistent with molecular structure of PheRS which is a tetramer including both FARSA and FARSB proteins.

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Section: Discussionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 81%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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FARSA mutations mimic phenylalanyl‐tRNA synthetase deficiency caused by FARSB defects

et al. 2019

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

Markovitz

Ghosh

Kuo

et al. 2020

American J of Med Genetics Pt A

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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.

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Severe course with lethal hepatocellular injury and skeletal muscular dysgenesis in a neonate with infantile liver failure syndrome type 1 caused by novel LARS1 mutations

Hirata

Okamoto

Ichikawa

et al. 2020

American J of Med Genetics Pt A

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Infantile liver failure syndrome type 1 (ILFS1) is a recently recognized autosomal recessive disorder caused by deleterious mutations in the leucyl‐tRNA synthetase 1 gene (LARS1). The LARS1 enzyme is responsible for incorporation of the amino acid leucine during protein polypeptide synthesis. Individuals with LARS1 mutations typically show liver failure from infancy to early childhood during periods of illness or other physiological stress. While 25 patients from 15 families with ILFS1 have been reported in the literature, histological reports from autopsy findings are limited. We report here a premature male neonate who presented with severe intrauterine growth retardation, microcytic anemia, and fulminant liver failure, and who was a compound heterozygote for two novel deleterious mutations in LARS1. An autopsy showed fulminant hepatitis‐like hepatocellular injury and fibrogenesis in the liver and a lack of uniformity in skeletal muscle, accompanied by the disruption of striated muscle fibers. Striking dysgenesis in skeletal muscle detected in the present case indicates the effect of LARS1 functional deficiency on the musculature. Whole‐exome sequencing may be useful for neonates with unexplained early liver failure if extensive genetic and metabolic testing is inconclusive.

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Aminoacyl-tRNA synthetase deficiencies in search of common themes

Cited by 90 publications

References 63 publications

FARSA mutations mimic phenylalanyl‐tRNA synthetase deficiency caused by FARSB defects

FARSA mutations mimic phenylalanyl‐tRNA synthetase deficiency caused by FARSB defects

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

Severe course with lethal hepatocellular injury and skeletal muscular dysgenesis in a neonate with infantile liver failure syndrome type 1 caused by novel LARS1 mutations

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