CMT2Q-causing mutation in the Dhtkd1 gene lead to sensory defects, mitochondrial accumulation and altered metabolism in a knock-in mouse model.

Publisher: BioMed Central Country of Publication: England NLM ID: 101610673 Publication Model: Electronic Cited Medium: Internet ISSN: 2051-5960 (Electronic) Linking ISSN: 20515960 NLM ISO Abbreviation: Acta Neuropathol Commun Subsets: MEDLINE

Original Publication: London : BioMed Central, [2013]-

Disease Models, Animal* ; Mice*; Charcot-Marie-Tooth Disease/*genetics ; Ketoglutarate Dehydrogenase Complex/*genetics ; Mitochondria/*pathology ; Sciatic Nerve/*metabolism ; Somatosensory Disorders/*genetics; Animals ; Axons/pathology ; Axons/ultrastructure ; Charcot-Marie-Tooth Disease/pathology ; Charcot-Marie-Tooth Disease/physiopathology ; Codon, Nonsense ; Energy Metabolism ; Gene Knock-In Techniques ; Ketoglutarate Dehydrogenase Complex/metabolism ; Mice, Transgenic ; Microscopy, Electron, Transmission ; Mitochondria/metabolism ; Mitochondria/ultrastructure ; Mitochondria, Muscle/metabolism ; Mitochondria, Muscle/pathology ; Mitochondria, Muscle/ultrastructure ; Muscle, Skeletal/metabolism ; Muscle, Skeletal/pathology ; Muscle, Skeletal/ultrastructure ; Myelin Sheath/pathology ; Myelin Sheath/ultrastructure ; Neural Conduction ; Nonsense Mediated mRNA Decay/genetics ; Peripheral Nerves/pathology ; Peripheral Nerves/ultrastructure ; Phenotype ; Point Mutation ; Sciatic Nerve/pathology ; Sciatic Nerve/ultrastructure ; Somatosensory Disorders/pathology ; Somatosensory Disorders/physiopathology

Charcot-Marie-Tooth disease (CMT) is a group of inherited neurological disorders of the peripheral nervous system. CMT is subdivided into two main types: a demyelinating form, known as CMT1, and an axonal form, known as CMT2. Nearly 30 genes have been identified as a cause of CMT2. One of these is the 'dehydrogenase E1 and transketolase domain containing 1' (DHTKD1) gene. We previously demonstrated that a nonsense mutation [c.1455 T > G (p.Y485*)] in exon 8 of DHTKD1 is one of the disease-causing mutations in CMT2Q (MIM 615025). The aim of the current study was to investigate whether human disease-causing mutations in the Dhtkd1 gene cause CMT2Q phenotypes in a mouse model in order to investigate the physiological function and pathogenic mechanisms associated with mutations in the Dhtkd1 gene in vivo. Therefore, we generated a knock-in mouse model with the Dhtkd1 ^Y486* point mutation. We observed that the Dhtkd1 expression level in sciatic nerve of knock-in mice was significantly lower than in wild-type mice. Moreover, a histopathological phenotype was observed, reminiscent of a peripheral neuropathy, including reduced large axon diameter and abnormal myelination in peripheral nerves. The knock-in mice also displayed clear sensory defects, while no abnormalities in the motor performance were observed. In addition, accumulation of mitochondria and an elevated energy metabolic state was observed in the knock-in mice. Taken together, our study indicates that the Dhtkd1 ^Y486* knock-in mice partially recapitulate the clinical phenotypes of CMT2Q patients and we hypothesize that there might be a compensatory effect from the elevated metabolic state in the knock-in mice that enables them to maintain their normal locomotor function.

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31571295 International Innovative Research Group Project of the National Natural Science Foundation of China; 2011BAI15B02 International Ministry of Science and Technology

0 (Codon, Nonsense)
EC 1.2.4.2 (Dhtkd1 protein, mouse)
EC 1.2.4.2 (Ketoglutarate Dehydrogenase Complex)

Date Created: 20200315 Date Completed: 20210115 Latest Revision: 20210202

20250114

PMC7071680

10.1186/s40478-020-00901-0

32169121