CMT 2A: Expression of mitofusin 2R94Q in a transgenic mouse leads to CMT 2A

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Brain. 2010 May;133(Pt 5):1460-9.

Expression of mitofusin 2R94Q in a transgenic mouse leads to Charcot-Marie-Tooth

neuropathy type 2A.

Cartoni R, Arnaud E, Médard JJ, Poirot O, Courvoisier DS, Chrast R, ou JC.

Department of Cell Biology, University of Geneva, 30 quai Ernest-Ansermet, 1211

Genève 4, Switzerland. jean-claude.martinou@....

Abstract

Charcot-Marie-Tooth disease type 2A is an autosomal dominant axonal form of

peripheral neuropathy caused by mutations in the mitofusin 2 gene.

Mitofusin 2 encodes a mitochondrial outer membrane protein that participates in

mitochondrial fusion in mammalian cells. How mutations in this protein lead to

Charcot-Marie-Tooth disease type 2A pathophysiology remains unclear.

We have generated a transgenic mouse expressing either a mutated (R94Q) or

wild-type form of human mitofusin 2 in neurons to evaluate whether the R94Q

mutation was sufficient for inducing a Charcot-Marie-Tooth disease type 2A

phenotype. Only mice expressing mitofusin 2(R94Q) developed locomotor

impairments and gait defects thus mimicking the Charcot-Marie-Tooth disease type

2A neuropathy.

In these animals, the number of mitochondria per axon was significantly

increased in the distal part of the sciatic nerve axons with a diameter smaller

than 3.5 mum.

Importantly, the analysis of R94Q transgenic animals also revealed an

age-related shift in the size of myelinated axons leading to an

over-representation of axons smaller than 3.5 mum. Together these data suggest a

link between an increased number of mitochondria in axons and a shift in axonal

size distribution in mitofusin 2(R94Q) transgenic animals that may contribute to

their neurological phenotype.