C1orf194 deficiency leads to incomplete early embryonic lethality and dominant intermediate Charcot–Marie–Tooth disease in a knockout mouse model

Abstract

Charcot-Marie-Tooth (CMT) disease is the most common inherited peripheral neuropathy, and shows clinical and genetic heterogeneity. Mutations in C1orf194 encoding a Ca2+ regulator in neurons and Schwann cells have been reported previously by us to cause CMT disease. In here, we further investigated the function and pathogenic mechanism of C1or194 by generating C1orf194 knockout (KO) mice. Homozygous mutants of C1orf194 mice exhibited incomplete embryonic lethality, characterized by differentiation abnormalities and stillbirth on embryonic days 7.5 to 15.5. Heterozygous and surviving homozygous C1orf194 KO mice developed motor and sensory defects at the age of 4 months. Electrophysiologic recordings showed decreased compound muscle action potential and motor nerve conduction velocity in the sciatic nerve of C1orf194-deficient mice as a pathologic feature of dominant intermediate-type CMT. Transmission electron microscopy analysis revealed demyelination and axonal atrophy in the sciatic nerve as well as swelling and loss of mitochondrial matrix and other abnormalities in axons and Schwann cells. A histopathologic examination showed a loss of motor neurons in the anterior horn of the spinal cord and muscle atrophy. Shorter internodal length between nodes of Ranvier and Schmidt-Lanterman incisures (SLIs) were detected in the sciatic nerve of affected animals. These results indicate that C1orf194 KO mice can serve as an animal model of CMT with a severe dominant intermediate CMT phenotype that can be used investigate the molecular mechanisms of the disease and evaluate the efficacy of therapeutic strategies.

De novo identification of mammalian ciliary motility proteins using cryo-EM

“… SUPPORTING CITATIONS The following references appear in the Supplemental information : Austin-Tse et al (2013) ; Barrodia et al (2018) ; Chen et al (2020) ; Chiani et al (2019) ; Dougherty et al (2020) ; Gonsales et al (2020) ; Hirschner et al (2007) ; Huang et al (2020) ; Jerber et al (2014) ; Jungnickel et al (2018) ; Knowles et al (2013) ; Leslie et al (2020) ; Li et al (2020) ; Lorenzetti et al (2004) ; Reish et al (2016) ; Ryan et al (2018) ; Sasaki et al (2019) ; Shamseldin et al (2020) ; Silva et al (2016) ; Sun et al (2019) ; Suzuki et al (2009) ; Ta-Shma et al (2015) ; Ta-Shma et al (2018) ; Vogel et al (2010) ; Wilson et al (2010) ; Wu and Singaraja (2013) ; Xu et al (2015) ; Zhang et al (2019) . …”

Addressing the Need of a Translational Approach in Peripheral Neuropathy Research: Morphology Meets Function

“…The algorithm we proposed can be considered more comprehensive in respect to the others previously described. In the vast majority, only the motor system (most frequently one nerve) [28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43] or only the sensory or mixed nerves [12,[44][45][46][47] were tested. A few groups tested both the motor and sensory systems, but none of the tests were performed at the same time as EMG recordings [48][49][50][51][52][53][54].…”