GDAP1 protein causing CMT 4A, expressed in neurons + assoc. with mitochondria

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Hum Mol Genet. 2005 Mar 16;

GDAP1, the protein causing Charcot-Marie-Tooth disease type 4A, is

expressed in neurons and is associated with mitochondria.

Pedrola L, Espert A, Wu X, Claramunt R, Shy ME, Palau F.

Laboratory of Genetics and Molecular Medicine, Department of Genomics

and Proteomics, Instituto de Biomedicina, CSIC, Valencia, Spain.

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.