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Human Molecular Genetics Advance Access originally published online on March 16, 2005
Human Molecular Genetics 2005 14(8):1087-1094; doi:10.1093/hmg/ddi121
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© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org

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

Laia Pedrola1, Antonio Espert1, Xingyao Wu2, Reyes Claramunt1, Michael E. Shy2 and Francesc Palau1,*

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

* To whom correspondence should be addressed at: Department of Genomics and Proteomics, Instituto de Biomedicina, CSIC, C/Jaume Roig 11, 46010 Valencia, Spain. Tel: +34 963393773; Fax: +34 963690800; Email: fpalau{at}ibv.csic.es

Received December 23, 2004; Revised February 14, 2005; Accepted March 3, 2005

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 in a human neuroblastoma cell line 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. 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 to the maintenance of the mitochondrial network.


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