Dominant GDAP1 mutations cause predominantly mild CMT phenotypes
| Autor: | David R. Cornblath, Nina Huber, Vincent Timmerman, Alice B. Schindler, E. Jaakkola, Dagmara Kabzińska, J. Pilch, Michaela Auer-Grumbach, Albena Jordanova, Andrzej Kochański, P. De Jonghe, Christian Guelly, Magdalena Zimoń, Irena Hausmanowa-Petrusewicz, Ueli Suter, Gian Maria Fabrizi, Axel Niemann, Kenneth H. Fischbeck, E. De Vriendt, Jonathan Baets |
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| Rok vydání: | 2011 |
| Předmět: |
DNA Mutational Analysis
Nerve Tissue Proteins Paternity Disease Biology medicine.disease_cause Article Cohort Studies 03 medical and health sciences Exon 0302 clinical medicine Charcot-Marie-Tooth Disease Chlorocebus aethiops medicine Animals Humans Allele Ganglioside-induced differentiation associated-protein 1 (GDAP1) mutations autosomal recessive Charcot-Marie-Tooth (ARCMT) neuropathy autosomal dominant Charcot-Marie-Tooth (ADCMT) Genes Dominant 030304 developmental biology Genetics 0303 health sciences Mutation Reverse Transcriptase Polymerase Chain Reaction Haplotype Exons Penetrance Phenotype Axons Introns Mitochondria Pedigree 3. Good health Haplotypes COS Cells Mutation testing Human medicine Neurology (clinical) 030217 neurology & neurosurgery HeLa Cells |
| Zdroj: | Neurology |
| ISSN: | 0028-3878 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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