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

Abstract

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.

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

“…Intrauterine growth retardation and postnatal growth restriction, as in our patient, are one of the most consistent symptoms of aaRSs deficiencies . Our patient was small for gestational age and had failure to thrive postnatally which is similar to two FARSB patients reported previously …”

“…All reported aaRSs deficiencies cause extensive brain lesions and/or sensory organ deficits . In the FARSB patients, brain calcifications were the most frequent symptoms followed by leukoencephalopathy and either cerebral volume loss and incomplete closure of Sylvian fissure or hydrocephalus or brain aneurysms . In our patient, brain MRI revealed abnormalities consistent with those reported in the FARSB patients.…”

“…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. Notably, none of the reported patients with the FARSB disease had biallelic null loss‐of‐function variants …”

“…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). 3,5,9 However, so far, there is no description of the FARSA-associated disease.…”

Homozygosity for FARSB mutation leads to Phe-tRNA synthetase-related disease of growth restriction, brain calcification, and interstitial lung disease

“…Recently, Xu et al. () reported on five affected individuals from four families. The phenotype consists of multi‐organ manifestations of interstitial lung disease with cholesterol pneumonitis, diffuse cerebral calcifications, hypotonia, and liver cirrhosis caused by biallelic mutations in FARSB .…”