AR-CMT2C: A new missense GDAP1 mutation disturbing targeting to the mitochondria

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Neurogenetics. 2011 Mar 2. [Epub ahead of print]

A new missense GDAP1 mutation disturbing targeting to the mitochondrial membrane

causes a severe form of AR-CMT2C disease.

Kabziñska D, Niemann A, Drac H, Huber N, Potulska-Chromik A,

Hausmanowa-Petrusewicz I, Suter U, Kochañski A.

Neuromuscular Unit, Mossakowski Medical Research Centre, Polish Academy of

Sciences, Warsaw, Poland.

Abstract

Charcot-Marie-Tooth disease (CMT) caused by mutations in the ganglioside-induced

differentiation-associated protein 1 (GDAP1) gene is characterized by a spectrum

of phenotypes. Recurrent nonsense mutations (Q163X and S194X) showing regional

distribution segregate with an early onset, severe course of recessive CMT

disease with early loss of ambulancy.

Missense mutations in GDAP1 have been reported in sporadic CMT cases with

variable course of disease, among them the recurrent L239F missense GDAP1

mutation occurring in the European population.

Finally, some GDAP1 mutations are associated with a mild form of CMT inherited

as an autosomal dominant trait.

In this study, we characterize the CMT phenotype in one Polish family with

recessive trait of inheritance at the clinical, electrophysiological,

morphological, cellular, and genetic level associated with a new Gly327Asp

mutation in the GDAP1 gene. In spite of the nature of Gly327Asp mutation

(missense), the CMT phenotype associated with this variant may be characterized

as an early onset, severe axonal neuropathy, with severe skeletal deformities.

The mutation lies within the transmembrane domain of GDAP1 and interferes with

the mitochondrial targeting of the protein, similar to the loss of the domain in

the previously reported Q163X and S194X mutations.

We conclude that the loss of mitochondrial targeting is associated with a severe

course of disease. Our study shows that clinical outcome of CMT disease caused

by mutations in the GDAP1 gene cannot be predicted solely on the basis of

genetic results (missense/nonsense mutations).