Biallelic Mutations of Methionyl-tRNA Synthetase Cause a Specific Type of Pulmonary Alveolar Proteinosis Prevalent on Réunion Island

Abstract

Methionyl-tRNA synthetase (MARS) catalyzes the ligation of methionine to tRNA and is critical for protein biosynthesis. We identified biallelic missense mutations in MARS in a specific form of pediatric pulmonary alveolar proteinosis (PAP), a severe lung disorder that is prevalent on the island of Réunion and the molecular basis of which is unresolved. Mutations were found in 26 individuals from Réunion and nearby islands and in two families from other countries. Functional consequences of the mutated alleles were assessed by growth of wild-type and mutant strains and methionine-incorporation assays in yeast. Enzyme activity was attenuated in a liquid medium without methionine but could be restored by methionine supplementation. In summary, identification of a founder mutation in MARS led to the molecular definition of a specific type of PAP and will enable carrier screening in the affected community and possibly open new treatment opportunities.

Predicting the pathogenicity of aminoacyl-tRNA synthetase mutations

“…Yeast complementation assays have been used to demonstrate a loss-of-function effect on ARS function for mutations in eight genes implicated in recessive diseases ( AARS , AARS2 , HARS2 , IARS , KARS , LARS2 , MARS , VARS2 ) [6,44,47,48,52,57,63,64]. Similar to aminoacylation assays, in vivo studies in yeast have revealed a loss-of-function effect for GARS , YARS , AARS , and HARS mutations that cause dominant CMT disease (Table 2).…”

“…Yeast assays also provide a rapid, tractable system to screen for molecules that can improve ARS function. Indeed, supplementation with methionine improved the in vivo function of mutant methionyl-tRNA synthetase ( MARS ) alleles that cause pulmonary alveolar proteinosis [52]. Finally, current worm and fly models rely on over-expression of the mutant allele to test for pathogenicity.…”

Pulmonary Alveolar Proteinosis Syndrome

“…Surfactant production disorders are less common and are caused by genetic mutations in genes that encode surfactant proteins or proteins involved in surfactant lipid metabolism, e.g., mutations in the SFTPB, SFTPC, ABCA3 or Nkx2.1 genes. Other genetic defects such as y+LAT1 ( SLC7A7 ) gene mutations which causes lysinuric protein intolerance 18 and Methionyl-tRNA synthetase ( MARS ) gene mutations 19 were reported to be associated with PAP. The precise mechanisms of PAP pathogenesis induced by these gene mutations have not been elucidated.…”

Children’s Interstitial and Diffuse Lung Disease. Progress and Future Horizons

“…As the human genome has become more accessible to discovery, new clinically relevant chILD gene abnormalities have been reported to include FLNA (filamin A, alpha) mutations that lead to lethal cystic lung disease (34,35), MARS (Methionyl-tRNA synthetase) mutations that cause severe pediatric PAP (36), COPA (Coatomer subunit alpha) mutations resulting in a syndrome of autoimmunity with arthritis, vasculitis and chILD (37), GATA-2 transcription factor mutations resulting in immunodeficiencies with monocytopenia, infections, lymphatic abnormalities, chILD and PAP (38)(39)(40) and LRBA (lipopolysaccharide-responsive and beige-like anchor protein) mutations causing immune mediated lung disease (41). This trend will only accelerate with more advanced genetic testing including whole exome sequencing in chILD syndrome.…”