Hadchouel Alice, Wieland Thomas, Griese Matthias, Baruffini Enrico, Lorenz-Depiereux Bettina, Enaud Laurent, Graf Elisabeth, Dubus Jean Christophe, Halioui-Louhaichi Sonia, Coulomb Aurore, Delacourt Christophe, Eckstein Gertrud, Zarbock Ralf, Schwarzmayr Thomas, Cartault François, Meitinger Thomas, Lodi Tiziana, de Blic Jacques, Strom Tim M
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.
Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
Am J Hum Genet. 2015 May 7;96(5):826-31. doi: 10.1016/j.ajhg.2015.03.010. Epub 2015 Apr 23.
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.
甲硫氨酰 - tRNA合成酶（MARS）催化甲硫氨酸与tRNA的连接，对蛋白质生物合成至关重要。我们在一种特定类型的儿童肺泡蛋白沉积症（PAP）中鉴定出MARS的双等位基因错义突变，PAP是一种严重的肺部疾病，在留尼汪岛很常见，其分子基础尚未明确。在来自留尼汪岛及附近岛屿的26名个体以及来自其他国家的两个家族中发现了突变。通过野生型和突变菌株的生长以及酵母中的甲硫氨酸掺入试验评估了突变等位基因的功能后果。在无甲硫氨酸的液体培养基中酶活性减弱，但补充甲硫氨酸后可恢复。总之，MARS中奠基者突变的鉴定导致了一种特定类型PAP的分子定义，并将使受影响社区能够进行携带者筛查，还可能带来新的治疗机会。
