ArticleHuman molecular genetics2013
A new locus for X-linked dominant Charcot-Marie-Tooth disease (CMTX6) is caused by mutations in the pyruvate dehydrogenase kinase isoenzyme 3 (PDK3) gene.
Article in Human molecular genetics, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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Who cites it
38 citing papers in PubMed, 82 citations in OpenAlex.
- Consensus Guidelines for Diagnosis and Management of Pyruvate Dehydrogenase Complex Deficiency.Journal of inherited metabolic disease · 2026Review
- A high-content phenotypic screen identifies luteolin as a repurposed drug to reduce pyruvate dehydrogenase phosphorylation and enhance energy production in CMTX6 cell models.Journal of molecular cell biology · 2026Article
- Junctions in Jeopardy: the neuromuscular junction is a selective pathological target in Charcot-Marie-Tooth disease.Mammalian genome : official journal of the International Mammalian Genome Society · 2026Review
- Animal models of pyruvate dehydrogenase complex deficiency: insight into mechanisms of cerebral abnormalities and tissue-specific role in metabolism.Frontiers in medicine · 2026Review
- Mitochondrial disease management through phytochemical interventions.Molecular and cellular biochemistry · 2025Review
- Genetic spectrum among 2009 Iranian individuals with neuromuscular disorders using next generation sequencing and multiple ligation dependent probe amplification methods.Scientific reports · 2025Article
- Random X chromosome inactivation in female Charcot-Marie-Tooth disease type X1: insights from sural nerve biopsy analysis.BMC neurology · 2025Article
- Synchronized long-read genome, methylome, epigenome and transcriptome profiling resolve a Mendelian condition.Nature genetics · 2025Article
- Spatial Fluctuation of Central Nervous System Lesions in X-linked Charcot-Marie-Tooth Disease with a Novel GJB1 Mutation.Internal medicine (Tokyo, Japan) · 2024Article
- Mitochondrial Alpha-Keto Acid Dehydrogenase Complexes: Recent Developments on Structure and Function in Health and Disease.Sub-cellular biochemistry · 2024Review
- Review
- A Missense Variant inBiomedicines · 2022Article
- Mitochondrial biology and dysfunction in secondary mitochondrial disease.Open biology · 2022Review
- Pyruvate Dehydrogenase Kinase Protects Dopaminergic Neurons from Oxidative Stress inMolecules and cells · 2022Article
- Detection of repeat expansions in large next generation DNA and RNA sequencing data without alignment.Scientific reports · 2022Article
- GDAP1 loss of function inhibits the mitochondrial pyruvate dehydrogenase complex by altering the actin cytoskeleton.Communications biology · 2022Article
- Structural Variation at a Disease Mutation Hotspot: Strategies to Investigate Gene Regulation and the 3D Genome.Frontiers in genetics · 2022Review
- Charcot-Marie-tooth disease causing mutation (p.R158H) in pyruvate dehydrogenase kinase 3 (PDK3) affects synaptic transmission, ATP production and causes neurodegeneration in a CMTX6 C. elegans model.Human molecular genetics · 2021Article
- Pyruvate dehydrogenase kinases (PDKs): an overview toward clinical applications.Bioscience reports · 2021Review
- Recent Advances inInternational journal of molecular sciences · 2020Review
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Authors and funding
13 authors at 7 institutions in 2 countries.
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Abstract
Hereditary motor and sensory disorders of the peripheral nerve form one of the most common groups of human genetic diseases collectively called Charcot-Marie-Tooth (CMT) neuropathy. Using linkage analysis in a three generation kindred, we have mapped a new locus for X-linked dominant CMT to chromosome Xp22.11. A microsatellite scan of the X chromosome established significant linkage to several markers including DXS993 (Zmax = 3.16; θ = 0.05). Extended haplotype analysis refined the linkage region to a 1.43-Mb interval flanked by markers DXS7110 and DXS8027. Whole exome sequencing identified a missense mutation c.G473A (p.R158H) in the pyruvate dehydrogenase kinase isoenzyme 3 (PDK3) gene. The change localized within the 1.43-Mb linkage interval, segregated with the affected phenotype and was excluded in ethnically matched control chromosomes. PDK3 is one of the four isoenzymes regulating the pyruvate dehydrogenase complex (PDC), by reversible phosphorylation, and is a nuclear-coded protein located in the mitochondrial matrix. PDC catalyzes the oxidative decarboxylation of pyruvate to acetyl CoA and is a key enzyme linking glycolysis to the energy-producing Krebs cycle and lipogenic pathways. We found that the R158H mutation confers enzyme hyperactivity and binds with stronger affinity than the wild-type to the inner-lipoyl (L2) domain of the E2p chain of PDC. Our findings suggest a reduced pyruvate flux due to R158H mutant PDK3-mediated hyper-phosphorylation of the PDC as the underlying pathogenic cause of peripheral neuropathy. The results highlight an important causative link between peripheral nerve degeneration and an essential bioenergetic or biosynthetic pathway required for the maintenance of peripheral nerves.
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