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

2015; Elsevier BV; Volume: 96; Issue: 5 Linguagem: Inglês

10.1016/j.ajhg.2015.03.010

1537-6605

Alice Hadchouel, Thomas Wieland, Matthias Griese, Enrico Baruffini, Bettina Lorenz‐Depiereux, Laurent Enaud, Elisabeth Graf, J.‐C. Dubus, S. Halioui-Louhaichi, Aurore Coulomb, Christophe Delacourt, Gertrud Eckstein, Ralf Zarbock, Thomas Schwarzmayr, François Cartault, Thomas Meitinger, Tiziana Lodi, J. de Blic, Tim M. Strom,

Medical Imaging and Pathology Studies

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.