title: Behavioral and molecular exploration of the AR-CMT2A mouse model Lmna (R298C/R298C).
abstract: In 2002, we identified LMNA as the first gene responsible for an autosomal recessive axonal form of Charcot-Marie-Tooth disease, AR-CMT2A. All patients were found to be homozygous for the same mutation in the LMNA gene, p.Arg298Cys. In order to investigate the physiopathological mechanisms underlying AR-CMT2A, we have generated a knock-in mouse model for the Lmna p.Arg298Cys mutation. We have explored these mice through an exhaustive series of behavioral tests and histopathological analyses, but were not able to find any peripheral nerve phenotype, even at 18 months of age. Interestingly at the molecular level, however, we detect a downregulation of the Lmna gene in all tissues tested from the homozygous knock-in mouse Lmna (R298C/R298C) (skeletal muscle, heart, peripheral nerve, spinal cord and cerebral trunk). Importantly, we further reveal a significant upregulation of Pmp22, specifically in the sciatic nerves of Lmna (R298C/R298C) mice. These results indicate that, despite the absence of a perceptible phenotype, abnormalities exist in the peripheral nerves of Lmna (R298C/R298C) mice that are absent from other tissues. Although the mechanisms leading to deregulation of Pmp22 in Lmna (R298C/R298C) mice are still unclear, our results support a relation between Lmna and Pmp22 and constitute a first step toward understanding AR-CMT2A physiopathology.
authors.affiliation: UMR_S 910, Génétique Médicale et Génomique Fonctionnelle, Inserm, 13385 Marseille cedex 05, France.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Poitelon
authors.forename: Serguei
authors.initials: S
authors.lastname: Kozlov
authors.forename: Jerôme
authors.initials: J
authors.lastname: Devaux
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Vallat
authors.forename: Marc
authors.initials: M
authors.lastname: Jamon
authors.forename: Pierre
authors.initials: P
authors.lastname: Roubertoux
authors.forename: Sitraka
authors.initials: S
authors.lastname: Rabarimeriarijaona
authors.forename: Cécile
authors.initials: C
authors.lastname: Baudot
authors.forename: Tarik
authors.initials: T
authors.lastname: Hamadouche
authors.forename: Colin L
authors.initials: CL
authors.lastname: Stewart
authors.forename: Nicolas
authors.initials: N
authors.lastname: Levy
authors.forename: Valérie
authors.initials: V
authors.lastname: Delague
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics* / Q000503:physiopathology / Q000523:psychology; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D055879:Gene Knock-In Techniques; D034904:Lamin Type A / Q000235:genetics / Q000502:physiology*; D051379:Mice; D009185:Myelin Proteins / Q000096:biosynthesis; D012584:Sciatic Nerve / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology
chemical_list: D034904:Lamin Type A; D009185:Myelin Proteins; C489545:Pmp22 protein, mouse