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Background: Progressive myoclonus epilepsy (PME) is a neurodegenerative disorder marked by recurrent seizures and progressive myoclonus. To date, based on the phenotypes and causal genes, more than 40 subtypes of PMEs have been identified, and more remain to be characterized. Our study is aimed at identifying the aberrant gene(s) possibly associated with PMEs in two siblings born to asymptomatic parents, in the absence of known genetic mutations. Methods: Clinical assessments and molecular analyses, such as the repeat expansion test for CSTB ; SCA1, 2, 3, 6, and 7; whole exome sequencing (WES); and mitochondrial genome sequencing coupled with computational analysis, were performed. Results: A family-based segregation analysis of WES data was performed to identify novel genes associated with PMEs. The potassium channel, KCNH8 [c.298T>C; (p.Tyr100His)], a DNA repair gene, regulator of telomere elongation helicase 1 ( RTEL1 ) [c.691G>T; (p.Asp231Tyr)] and long noncoding RNA, RTEL1-TNFRSF6B [chr20:62298898_G>T; NR_037882.1, hg19] were among the candidate genes that were found to be associated with PMEs. These homozygous variations in siblings belong to genes with a loss-of-function intolerant (pLI) score of ≤ 0.86, expected to be detrimental by multiple computational analyses, and were heterozygous in parents. Additionally, computational analysis and the expression of RTEL1 and RTEL1-TNFRSF6B revealed that RTEL1-TNFRSF6B may modulate RTEL1 via hsa-miR-3529-3p. In the patient with the severe phenotype, a further deleterious mutation in SLC22A17 was identified. No de novo variants specific to these probands were identified in the mitochondrial genome. Conclusions: Our study is the first to report variants in KCNH8 , RTEL1 , and RTEL1-TNFRSF6B among PME cases. These genes when characterized fully may shed light on pathogenicity and have the potential to be used in the diagnosis of PME., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Sima Chaudhari et al.)

PRIP Interacting protein with Methyl Transferase domain (PIMT/TGS1) is an integral upstream coactivator in the peroxisome proliferator-activated receptor gamma (PPARγ) transcriptional apparatus. PPARγ activation alleviates insulin resistance but promotes weight gain. Herein, we show how PIMT regulates body weight while promoting insulin sensitivity in diet induced obese mice. In vitro, we observed enhanced PIMT levels during adipogenesis. Knockdown of PIMT in 3T3-L1 results in reduced lipid accumulation and alters PPARγ regulated gene expression. Intraperitoneal injection of shPIMT lentivirus in high fat diet (HFD)-fed mice caused reduced adipose tissue size and decreased expression of lipid markers. This was accompanied by significantly lower levels of inflammation, hypertrophy and hyperplasia in the different adipose depots (eWAT and iWAT). Notably, PIMT depletion limits body weight gain in HFD-fed mice along with improved impaired oral glucose clearance. It also enhanced insulin sensitivity revealed by assessment of important insulin resistance markers and increased adiponectin levels. In addition, reduced PIMT levels did not alter the serum free fatty acid and TNFα levels. Finally, the relevance of our studies to human obesity is suggested by our finding that PIMT was upregulated in adipose tissue of obese patients along with crucial fat marker genes. We speculate that PIMT may be a potential target in maintaining energy metabolism, thus regulating obesity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Choreoacanthocytosis, one of the forms of neuroacanthocytosis, is caused by mutations in vacuolar protein sorting-associated protein A (VPS13A), and is often misdiagnosed with other form of neuroacanthocytosis with discrete genetic defects. The phenotypic variations among the patients with VPS13A mutations significantly obfuscates the understanding of the disease and treatment strategies. In this study, two unrelated cases were identified, exhibiting the core phenotype of neuroacanthocytosis but with considerable clinical heterogeneity. Case 1 presented with an additional Parkinsonism phenotype, whereas seizures were evident in case 2. To decipher the genetic basis, whole exome sequencing followed by validation with Sanger sequencing was performed. A known homozygous pathogenic nonsense mutation (c.799C > T; p.R267X) in exon 11 of the VPS13A gene was identified in case 1 that resulted in a truncated protein. A novel missense mutation (c.9263T > G; p.M3088R) in exon 69 of VPS13A identified in case 2 was predicted as pathogenic. In silico analysis of the p.M3088R mutation at the C-terminus of VPS13A suggests a loss of interaction with TOMM40 and may disrupt mitochondrial localization. We also observed an increase in mitochondrial DNA copy numbers in case 2. Mutation analysis revealed benign heterozygous variants in interacting partners of VPS13A such as VAPA in case 1. Our study confirmed the cases as ChAc and identified the novel homozygous variant of VPS13A (c.9263T > G; p.M3088R) within the mutation spectrum of VPS13A-associated ChAc. Furthermore, mutations in VPS13A and co-mutations in its potential interacting partner(s) might contribute to the diverse clinical manifestations of ChAc, which requires further study., (© 2023. The Author(s).)