Fiche publication
Date publication
mai 2014
Auteurs
Membres identifiés du Cancéropôle Est :
Dr SORG Tania
Tous les auteurs :
Lopez-Delisle L, Pierre-Eugene C, Bloch-Gallego E, Birling MC, Duband JL, Durand E, Bourgeois T, Matrot B, Sorg T, Huerre M, Meziane H, Roux MJ, Champy MF, Gallego J, Delattre O, Janoueix-Lerosey I
Lien Pubmed
Résumé
The ALK (Anaplastic Lymphoma Kinase) gene encodes a tyrosine kinase receptor preferentially expressed in the central and peripheral nervous systems. A syndromic presentation associating congenital neuroblastoma with severe encephalopathy and an abnormal shape of the brainstem has been described in patients harbouring de novo germline F1174V and F1245V ALK mutations. Here, we investigated the phenotype of knock-in (KI) mice bearing the AlkF1178L mutation (F1174L in human). Although heterozygous KI mice did not reproduce the severe breathing and feeding difficulties observed in human patients, behavioral tests documented a reduced activity during dark phases and an increased anxiety of mutated mice. Matings of heterozygotes yielded the expected proportions of wild-type, heterozygotes and homozygotes at birth but a high neonatal lethality was noticed for homozygotes. We documented Alk expression in several motor nuclei of the brainstem involved in the control of sucking and swallowing. Evaluation of basic physiological functions 12 hours after birth revealed slightly more apneas but a dramatic reduced milk intake for homozygotes compared to control littermates. Overall, our data demonstrate that Alk activation above a critical threshold is not compatible with survival in mice, in agreement with the extremely severe phenotype of patients carrying aggressive de novo ALK germline mutations.
Référence
Oncotarget. 2014 May 15;5(9):2703-13.
