NDLI: A new missense GDAP1 mutation disturbing targeting to the mitochondrial membrane causes a severe form of AR-CMT2C disease

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A new missense GDAP1 mutation disturbing targeting to the mitochondrial membrane causes a severe form of AR-CMT2C disease

Content Provider	Springer Nature Link
Author	Kabzińska, Dagmara Niemann, Axel Drac, Hanna Huber, Nina Potulska Chromik, Anna Hausmawa Petrusewicz, Irena Suter, Ueli Kochański, Andrzej
Copyright Year	2011
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).
Starting Page	145
Ending Page	153
Page Count	9
File Format	PDF
ISSN	13646745
Journal	Neurogenetics
Volume Number	12
Issue Number	2
e-ISSN	13646753
Language	English
Publisher	Springer-Verlag
Publisher Date	2011-03-02
Publisher Place	Berlin, Heidelberg
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	GDAP1 mutations Phenotype–genotype correlations Mitochondrial targeting Tail-anchored protein Transmembrane domain Neurosciences Human Genetics Molecular Medicine
Content Type	Text
Resource Type	Article
Subject	Genetics Cellular and Molecular Neuroscience Genetics (clinical)

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