Behavioral and molecular exploration of the AR-CMT2A mouse model Lmna (R298C/R298C).

Neuromolecular Medicine
Yannick PoitelonValérie Delague

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 ...Continue Reading

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Citations

Aug 15, 2014·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Howard J Worman, William T Dauer
Jun 21, 2013·Journal of the Peripheral Nervous System : JPNS·Meriem TazirJean-Michel Vallat
Jan 21, 2014·Seminars in Cell & Developmental Biology·Feriel AzibaniAnne T Bertrand
Jun 29, 2017·Glia·Gustavo Della-Flora NunesYannick Poitelon
Aug 3, 2016·Disease Models & Mechanisms·Dido CarreroCarlos López-Otín
Aug 6, 2019·Frontiers in Molecular Neuroscience·Belin SophiePoitelon Yannick
Nov 9, 2018·Frontiers in Physiology·Heather B Steele-StallardFrancesco Saverio Tedesco

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