caa a22 4500 445364750 CHVBK 20180317142926.0 cr unu---uuuuu 170323e20110501xx s 000 0 eng 10.1007/s10048-011-0276-7 doi (NATIONALLICENCE)springer-10.1007/s10048-011-0276-7 A new missense GDAP1 mutation disturbing targeting to the mitochondrial membrane causes a severe form of AR-CMT2C disease [Elektronische Daten] [Dagmara Kabzińska, Axel Niemann, Hanna Drac, Nina Huber, Anna Potulska-Chromik, Irena Hausmanowa-Petrusewicz, Ueli Suter, Andrzej Kochański] 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). Springer-Verlag, 2011 GDAP1 mutations nationallicence Phenotype-genotype correlations nationallicence Mitochondrial targeting nationallicence Tail-anchored protein nationallicence Transmembrane domain nationallicence Kabzińska Dagmara Neuromuscular Unit, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland aut Niemann Axel Institute of Cell Biology, ETH Zurich, Zurich, Switzerland aut Drac Hanna Neuromuscular Unit, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland aut Huber Nina Institute of Cell Biology, ETH Zurich, Zurich, Switzerland aut Potulska-Chromik Anna Department of Neurology, Medical University of Warsaw, Warsaw, Poland aut Hausmanowa-Petrusewicz Irena Neuromuscular Unit, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland aut Suter Ueli Institute of Cell Biology, ETH Zurich, Zurich, Switzerland aut Kochański Andrzej Neuromuscular Unit, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland aut neurogenetics Springer-Verlag 12/2(2011-05-01), 145-153 1364-6745 12:2<145 2011 12 10048 https://doi.org/10.1007/s10048-011-0276-7 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s10048-011-0276-7 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Kabzińska Dagmara Neuromuscular Unit, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland aut NATIONALLICENCE 700 1- Niemann Axel Institute of Cell Biology, ETH Zurich, Zurich, Switzerland aut NATIONALLICENCE 700 1- Drac Hanna Neuromuscular Unit, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland aut NATIONALLICENCE 700 1- Huber Nina Institute of Cell Biology, ETH Zurich, Zurich, Switzerland aut NATIONALLICENCE 700 1- Potulska-Chromik Anna Department of Neurology, Medical University of Warsaw, Warsaw, Poland aut NATIONALLICENCE 700 1- Hausmanowa-Petrusewicz Irena Neuromuscular Unit, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland aut NATIONALLICENCE 700 1- Suter Ueli Institute of Cell Biology, ETH Zurich, Zurich, Switzerland aut NATIONALLICENCE 700 1- Kochański Andrzej Neuromuscular Unit, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland aut NATIONALLICENCE 773 0- neurogenetics Springer-Verlag 12/2(2011-05-01), 145-153 1364-6745 12:2<145 2011 12 10048 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer