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Human Molecular Genetics Advance Access published online on March 16, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi121
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© The Author 2005. Published by Oxford University Press. All rights reserved

Article

GDAP1, the protein causing Charcot-Marie-Tooth disease type 4A, is expressed in neurons and is associated with mitochondria

Laia Pedrola 1, Antonio Espert 1, Xingyao Wu 2, Reyes Claramunt 1, Michael E. Shy 2, and Francesc Palau 1*

1 Laboratory of Genetics and Molecular Medicine, Department of Genomics and Proteomics, Instituto de Biomedicina, CSIC, Valencia, Spain
2 Department of Neurology and Centre for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI, USA

* To whom correspondence should be addressed.
Francesc Palau, E-mail: fpalau{at}ibv.csic.es


  Abstract

Mutations in GDAP1, the ganglioside-induced differentiation-associated protein 1 gene, cause Charcot-Marie-Tooth (CMT) type 4A, a severe autosomal recessive form of neuropathy associated with either demyelinating or axonal phenotypes. Here we demonstrate that GDAP1 has far greater expression in neurons than in myelinating Schwann cells. We investigated cell localization of GDAP1 by means of transient overexpression and co-localization with organelle markers in COS-7 cells, and by Western blot analysis of subcell fractions with anti-GDAP1 polyclonal antibodies in a human neuroblastoma cell line. We observed that GDAP1 is localized in mitochondria. We also show that C-terminal transmembrane domains are necessary for the correct localization in mitochondria; however, missense mutations do not change the mitochondrial pattern of the wild-type protein. Our findings suggest that CMT4A disease is in fact a mitochondrial neuropathy mainly involving axons, and represents a disease belonging to the new category of mitochondrial disorders caused by mutations in nuclear genes. We postulate that GDAP1 may be related with the maintenance of the mitochondrial network.


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