Behavioral and Molecular Exploration of the AR-CMT2A Mouse Model Lmna (R298C/R298C)

Author:

Poitelon, Y.

Kozlov, S.

Devaux, J.

Vallat, J. M.

Jamon, M.

Roubertoux, P.

Rabarimeriarijaona, S.

Baudot, C.

Hamadouche, T.

Stewart, C. L.

Levy, N.

Delague, V.
Author Address

[Poitelon, Yannick; Jamon, Marc; Roubertoux, Pierre; Rabarimeriarijaona, Sitraka; Baudot, Cecile; Hamadouche, Tarik; Levy, Nicolas; Delague, Valerie] Aix Marseille Univ, Fac Med Timone, UMR S 910, F-13385 Paris 05, France. [Poitelon, Yannick; Jamon, Marc; Roubertoux, Pierre; Rabarimeriarijaona, Sitraka; Baudot, Cecile; Hamadouche, Tarik; Levy, Nicolas; Delague, Valerie] Fac Med Timone, INSERM, UMR S 910, F-13385 Paris 05, France. [Kozlov, Serguei] Canc Inst Frederick, Canc & Dev Biol Lab, Frederick, MD USA. [Devaux, Jerome] Aix Marseille Univ, IFR Jean Roche, UMR 6231, Dept Signalisat Neuronale,CRN2 M, F-13385 Paris 05, France. [Vallat, Jean-Michel] CHU Limoges, Ctr Reference Neuropathies Peripher Rares, Lab Neurol, Limoges, France. [Vallat, Jean-Michel] CHU Limoges, Ctr Reference Neuropathies Peripher Rares, Serv Neurol, Limoges, France. [Hamadouche, Tarik] Univ Alger, Lab Neurosci, Algiers, Algeria. [Hamadouche, Tarik] Univ Mhamed Bougara, Lab Biol Mol, Boumerdes, Algeria. [Stewart, Colin L.] A STAR Inst Med Biol, Singapore, Singapore. [Levy, Nicolas] Hop Enfants La Timone, AP HM, Dept Med Genet, Marseille, France.;Delague, V (reprint author), Aix Marseille Univ, Fac Med Timone, UMR S 910, 27 Blvd Jean Moulin, F-13385 Paris 05, France;valerie.delague@univ-amu.fr

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.

See More

Author Address