Efhc1 deficiency causes spontaneous myoclonus and increased seizure susceptibility

Abstract

Mutations in EFHC1 gene have been previously reported in patients with epilepsies, including those with juvenile myoclonic epilepsy. Myoclonin1, also known as mRib72-1, is encoded by the mouse Efhc1 gene. Myoclonin1 is dominantly expressed in embryonic choroid plexus, post-natal ependymal cilia, tracheal cilia and sperm flagella. In this study, we generated viable Efhc1-deficient mice. Most of the mice were normal in outward appearance, and both sexes were found to be fertile. However, the ventricles of the brains were significantly enlarged in the null mutants, but not in the heterozygotes. Although the ciliary structure was found intact, the ciliary beating frequency was significantly reduced in null mutants. In adult stages, both the heterozygous and null mutants developed frequent spontaneous myoclonus. Furthermore, the threshold of seizures induced by pentylenetetrazol was significantly reduced in both heterozygous and null mutants. These observations seem to further suggest that decrease or loss of function of myoclonin1 may be the molecular basis for epilepsies caused by EFHC1 mutations.

EFHC1 variants in juvenile myoclonic epilepsy: reanalysis according to NHGRI and ACMG guidelines for assigning disease causality

“…15 The diagram shows the domain organization of EFHC1 protein, the positions of various mutations found in JME families, and their frequency (number of independent families with a given mutation). Mutation numbering is based on the GenBank reference protein sequence with accession number 608816 EFHC1 function has been studied at the gene level by knocking out EFHC1 orthologs in both mice 59,60 and flies (Supplementary Table S7 online). 61 Both mouse and fly models presented seizure-related and electroclinical phenotypes and neuroanatomical measures similar to those in the variant-level functional studies.…”

“…Supplementary Table S7 online summarizes 20 gene-level experimental studies of efhc1-deficient mouse 59,60 and fly models. 61 The most impressive experimental evidence for disease causality seeing the epileptic disorder manifest in a knockout animal model.…”

“…Heterozygous (efhc1 +/− ) and null (efhc1 −/− ) mutants exhibit more spontaneous positive myoclonias than wild-type mice and quick, high-amplitude polyspikes on their EMG. 59 Two measures of seizure susceptibility-the percentage of animals exhibiting generalized seizures within 600 s after treatment with pentylenetretrazole (PTZ) and latency to clonic seizures after PTZ treatment-are significantly increased in the same measures of wild-type mice, with the greatest significance reached in 9-to 12-month-old mice. Both efhc1 +/− and efhc1 −/− mutant mice show ependymal cilia in the lateral ventricles, with abnormally decreased movements at 3 months and slightly enlarged lateral ventricles and decreased hippocampal volume at 12 months.…”

“…Both efhc1 +/− and efhc1 −/− mutant mice show ependymal cilia in the lateral ventricles, with abnormally decreased movements at 3 months and slightly enlarged lateral ventricles and decreased hippocampal volume at 12 months. 59 In mice with massive myoclonias and grand mal CTC convulsions, cell death occurs in ependymal cells along periventricular zones (both lateral and fourth ventricles) and in striatal cells, while disorganization of cell layering in paraventricular nucleus of hypothalamus, thalamus, hippocampus, and neocortex is present. 60 The notion of overgrown and overexcitable neurons and neurites was further examined in vivo in Drosophila melanogaster.…”

The regulation of ciliary beat frequency by ovarian steroids in the guinea pig Fallopian tube: interactions between oestradiol and progesterone

“…These observations may suggest that PRG and βE 2 also interact in regulating CBF in the fimbria. A light microscope that was connected to a highspeed (500 Hz) camera enabled us to directly observe the beating cilia of the epithelial surface, as was previously reported in the trachea, bronchiole, and brain ventricle (5,14,21,22). This method allows one to measure the CBF in the fimbria (15).…”