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

Am J Hum Genet. 2015 May 7;96(5):826-31. doi: 10.1016/j.ajhg.2015.03.010.

Alice Hadchouel ¹, Thomas Wieland ², Matthias Griese ³, Enrico Baruffini ⁴, Bettina Lorenz-Depiereux ², Laurent Enaud ⁵, Elisabeth Graf ², Jean Christophe Dubus ⁶, Sonia Halioui-Louhaichi ⁷, Aurore Coulomb ⁸, Christophe Delacourt ⁹, Gertrud Eckstein ², Ralf Zarbock ³, Thomas Schwarzmayr ², François Cartault ¹⁰, Thomas Meitinger ¹¹, Tiziana Lodi ⁴, Jacques de Blic ¹², Tim M Strom ¹³

Affiliations

1 Service de Pneumologie et d'Allergologie Pédiatriques, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, 75015 Paris, France; Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, 75006 Paris, France; INSERM U-1163, Team of Embryology and Genetics of Congenital Malformations, 75015 Paris, France; INSERM U-955, équipe 4, 94000 Créteil, France.
2 Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
3 Hauner Children's University Hospital, Ludwig-Maximilians-Universität, German Center for Lung Research, 80337 Munich, Germany.
4 Department of Life Sciences, University of Parma, 43124 Parma, Italy.
5 Department of Pediatrics, Centre Hospitalier Universitaire de La Réunion, 97410 Saint-Pierre, La Réunion, France.
6 Department of Pediatrics, Timone University Hospital, 13385 Marseille, France.
7 Department of Pediatrics, Mongi Slim Hospital La Marsa, University of Tunis El Manar, 1007 Tunis, Tunisia.
8 Service d'Anatomie et Cytologie Pathologiques, Hôpital d'Enfants Armand-Trousseau, Centre Hospitalier Universitaire de Paris-Est, Assistance Publique-Hôpitaux de Paris, 75012 Paris, France.
9 Service de Pneumologie et d'Allergologie Pédiatriques, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, 75015 Paris, France; INSERM U-955, équipe 4, 94000 Créteil, France; Université Paris-Descartes, 75006 Paris, France.
10 Service de Génétique, Centre Hospitalier Universitaire de la Réunion, 97400 Saint-Denis, La Réunion, France.
11 Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany.
12 Service de Pneumologie et d'Allergologie Pédiatriques, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, 75015 Paris, France; Université Paris-Descartes, 75006 Paris, France.
13 Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany. Electronic address: timstrom@helmholtz-muenchen.de.

PMID: 25913036 DOI: 10.1016/j.ajhg.2015.03.010

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.

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