EFHC1 mutation in Indian juvenile myoclonic epilepsy patient

Abstract

SummaryObjectiveJuvenile myoclonic epilepsy (JME) is the most common form of idiopathic generalized epilepsies (IGEs) and is genetically heterogeneous. Mutations in EFHC1 cause JME. Because about 2 million people in India are affected by JME alone, we investigated the prevalence of mutations in the EFHC1 gene in the Indian population with JME. We studied 63 patients with JME and 80 healthy controls.MethodsClinical identification of JME was evaluated using established criteria. Following clinical evaluation of the patients and confirming presence of JME, blood samples were collected from each patient and healthy individual. Subsequently, genomic DNA was extracted from the blood samples. Eleven exons of the EFHC1 gene were individually amplified by polymerase chain reaction (PCR) for each DNA sample. The PCR products were then purified and sequenced commercially. The identified DNA variants were sequenced at least twice in both the forward and reverse directions and compared with the Exome Aggregation Consortium (ExAC) database.ResultsWe found five heterozygous and one homozygous variant. We found three novel coding variants 661C→T, 779 G →A, and 730 C→T, which lead to R221C, R260Q, and R244STOP amino acid substitutions, respectively. The coding variant 475 C→T, resulting in the amino acid substitution R159W, reported earlier as polymorphism, was also identified in both patient and control populations.SignificanceDetection of these three novel variants, excluding R159W, which is considered polymorphism, expands the range of possible mutations in the EFHC1 gene. The novel variants that we are reporting herein have not been mentioned before as occurring in JME patients of other ethnic population. Therefore, these novel coding variants may be confined to the Indian JME population. Further studies on the mutational spectrum of EFHC1 in a larger number of Indian JME patients concurrent with their mode of inheritance and underlying functional assays should establish whether EFHC1 could be a panethnic gene for JME.

Subtle Brain Developmental Abnormalities in the Pathogenesis of Juvenile Myoclonic Epilepsy

“…Later on, new heterozygous mutations in EFHC1 were described in other Mexican, Honduras, and Japanese families but also in 3 unrelated Italian families and in 5 patients from Austria (Stogmann et al, 2006; Annesi et al, 2007; Medina et al, 2008; Jara-Prado et al, 2012). Recently two studies performed in India described 5 missense mutations in six independent families and 13 mutations in 28 patients (Raju et al, 2017; Thounaojam et al, 2017). While pathogenic variants of EFHC1 are present in 3% of Japanese JME patients, in 7 to 9% in JME patients from Mexico and Honduras and in 5% of JME patients from India, pathogenic variants of EFHC1 may be extremely rare in JME patients from Germany while possibly absent in the Dutch, Swedish, and United Kingdom populations.…”

Epilepsy protein myoclonin1 interacts with inositol 1,4,5–trisphosphate (IP3) receptor and reduces Ca2+store in endoplasmic reticulum

“…We originally and mistakenly reported that myoclonin1 is expressed in neurons of mouse brain (Suzuki et al, 2004), but our subsequent studies using Efhc1 -/mouse and a newly-developed mouse monoclonal antibody for myoclonin1 (6A3-mAb) revealed that myoclonin1 is actually not expressed in neurons but dominantly expressed in choroid plexus at embryonic stages, and at motile cilia of ependymal cells, tracheal motile cilia, and sperm flagella at postnatal stages Suzuki et al, 2009;Suzuki et al, 2020). EFHC1 heterozygous missense mutations in patients with epilepsies including JME have been repeatedly reported by us and many other groups (Suzuki et al, 2004;Ma et al, 2006;Stogmann et al, 2006;Annesi et al, 2007;Medina et al, 2008;Jara-Prado et al, 2012;Coll et al, 2016;Bailey et al, 2017;Raju et al, 2017;Thounaojam et al, 2017;Wang et al, 2017;Lin et al, 2023). A missense mutation in EFHC1 has also been identified homozygously in patients with intractable epilepsy of infancy (Berger et al, 2012).…”

Mutational Analysis of Myoclonin1 Gene in Pakistani Juvenile Myoclonic Epilepsy Patients

“…The mutations that have been reported in these genes were private mutations, only found in single families and typically of de novo origin, that are not spotted in biological parents. Importantly, these de novo mutations (DNMs) were not detected in other family-based association studies for JME in the same or different ethnicities [ 16 ]. Consequently, mutations in genes coding for ion channel proteins cannot be accounted as the common cause of JME.…”