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SHR Neuro Krebs Kardio Lipid Stoffw Microb

Zimon, M; Baets, J; Fabrizi, GM; Jaakkola, E; Kabzinska, D; Pilch, J; Schindler, AB; Cornblath, DR; Fischbeck, KH; Auer-Grumbach, M; Guelly, C; Huber, N; De Vriendt, E; Timmerman, V; Suter, U; Hausmanowa-Petrusewicz, I; Niemann, A; Kochanski, A; De Jonghe, P; Jordanova, A.
Dominant GDAP1 mutations cause predominantly mild CMT phenotypes.
Neurology. 2011; 77(6): 540-548. Doi: 10.1212/WNL.0b013e318228fc70 [OPEN ACCESS]
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Co-Autor*innen der Med Uni Graz
Auer-Grumbach Michaela
Gülly Christian

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Objective: Ganglioside-induced differentiation associated-protein 1 (GDAP1) mutations are commonly associated with autosomal recessive Charcot-Marie-Tooth (ARCMT) neuropathy; however, in rare instances, they also lead to autosomal dominant Charcot-Marie-Tooth (ADCMT). We aimed to investigate the frequency of disease-causing heterozygous GDAP1 mutations in ADCMT and their associated phenotype. Methods: We performed mutation analysis in a large cohort of ADCMT patients by means of bidirectional sequencing of coding regions and exon-intron boundaries of GDAP1. Intragenic GDAP1 deletions were excluded using an allele quantification assay. We confirmed the pathogenic character of one sequence variant by in vitro experiments assaying mitochondrial morphology and function. Results: In 8 Charcot-Marie-Tooth disease (CMT) families we identified 4 pathogenic heterozygous GDAP1 mutations, 3 of which are novel. Three of the mutations displayed reduced disease penetrance. Disease onset in the affected individuals was variable, ranging from early childhood to adulthood. Disease progression was slow in most patients and overall severity milder than typically seen in autosomal recessive GDAP1 mutations. Electrophysiologic changes are heterogeneous but compatible with axonal neuropathy in the majority of patients. Conclusions: With this study, we broaden the phenotypic and genetic spectrum of autosomal dominant GDAP1-associated neuropathies. We show that patients with dominant GDAP1 mutations may display clear axonal CMT, but may also have only minimal clinical and electrophysiologic abnormalities. We demonstrate that cell-based functional assays can be reliably used to test the pathogenicity of unknown variants. We discuss the implications of phenotypic variability and the reduced penetrance of autosomal dominant GDAP1 mutations for CMT diagnostic testing and counseling. Neurology (R) 2011;77:540-548
Find related publications in this database (using NLM MeSH Indexing)
Animals -
Axons - pathology
COS Cells -
Cercopithecus aethiops -
Charcot-Marie-Tooth Disease - genetics
Cohort Studies -
DNA Mutational Analysis -
Exons - genetics
Genes, Dominant -
Haplotypes -
HeLa Cells -
Humans -
Introns - genetics
Mitochondria - metabolism
Mutation -
Nerve Tissue Proteins - genetics
Paternity -
Pedigree -
Phenotype -
Reverse Transcriptase Polymerase Chain Reaction -

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