Biology subjects

Mavashov, A.

Publications and source records attributed to Mavashov, A..

4 recordsLinked to original sources

bioRxiv2025

Inducible formation of fusion transcripts upregulates haploinsufficient CHD2 gene expression

Modes of action of long noncoding RNAs (lncRNAs) are poorly understood. CHASERR is a broadly expressed lncRNA located immediately upstream of the promoter of the CHD2 gene. We show that antisense oligonucleotides (ASOs) targeting conserved motifs in CHASERRs last exon induce the formation of a fusion transcript joining CHASERR to CHD2. This fusion transcript is exported to the cytoplasm and translated into full-length CHD2 protein. Deleting the same motifs in mice mimics the ASO effect, increasing CHD2 protein without causing the deleterious effects associated with full CHASERR ablation. The fusion transcripts are also expressed endogenously, induced in activated neurons, and their constitutive induction affects neuronal gene expression and chromatin accessibility. Perinatal introduction of the ASO into Chd2+/- mice up-regulates CHD2 expression and alleviates behavioral phenotypes caused by CHD2 haploinsufficiency, providing a therapeutic route to CHD2 haploinsufficiency. This concept of targeting upstream genes with ASOs to induce transcript fusion can be extended to other gene pairs, and is thus a broadly relevant approach for increasing haploinsufficient gene expression.

molecular biology↗

bioRxiv2025

Alterations in background ECoG activity and behavioral deficits in a mouse model of CHD2-related developmental delay

Heterozygous loss of function mutations in the CHD2 gene, encoding for chromodomain helicase DNA-binding protein 2, are associated with severe childhood-onset epilepsy, global developmental delay, and autistic features. Here, we characterized the behavioral and epileptic phenotypes of a mouse model harboring a frameshift truncating mutation in the Chd2 gene (Chd2WT/m and Chd2m/m mice). Genetic background dramatically affected the phenotypes. While no phenotypes were observed on the pure C57BL/6J background, crossing these mice onto the 129X1/SvJ genetic background gradually uncovered neurodevelopmental phenotypes. Transcriptomic analysis identified Kcnj11 as a potential genetic modifier. On the 129X1/SvJ background, Chd2m/m mice demonstrated growth retardation, and both Chd2WT/m and Chd2m/m showed motor deficits, including clasping behavior and reduced abilities to balance on a rotating rod. Autistic-like features were also observed, with Chd2m/m showing reduced nest-building abilities and Chd2WT/m demonstrating increased repetitive-like behavior in the marble burying test and altered social behavior. Quantitative analysis of electrocorticographic (ECoG) recordings revealed neuronal changes consisting of a global reduction in the total power of background activity in Chd2WT/m and Chd2m/m mice, as well as increased susceptibility to seizures induced by acute administration of 4-aminopyridine. Overall, this mouse model recapitulates multiple key phenotypes observed in CHD2 patients, providing a valuable platform to study the molecular basis and treatment options for this intractable disease.

neuroscience↗

bioRxiv2023

Heat-induced seizures, premature mortality, and hyperactivity in a novel Scn1a nonsense model for Dravet syndrome

Dravet syndrome (Dravet) is a severe congenital developmental genetic epilepsy caused by de novo mutations in the SCN1A gene. Nonsense mutations are found in ~20% of the patients, and the R613X mutation was identified in multiple patients. Here we characterized the epileptic and non-epileptic comorbidities of a novel preclinical Dravet mouse model harboring this nonsense Scn1a mutation. Heterozygous Scn1a R613X mutation on a mixed C57BL/6J:129S1/SvImJ background exhibited spontaneous seizures, susceptibility to heat-induced seizures, and premature mortality, recapitulating the core epileptic phenotypes of Dravet. In addition, these mice, available as an open-access model, demonstrated increased locomotor activity in the open-field test, mimicking some non-epileptic Dravet-associated comorbidities. Conversely, Scn1aWT/R613X mice on the pure 129S1/SvImJ background had a normal life span and were easy to breed. Homozygous Scn1aR613X/R613X mice died before P16. Our molecular analyses of hippocampal and cortical expression demonstrated that the premature stop codon induced by the R613X mutation reduced Scn1a mRNA and Nav1.1 protein levels to ~50% in heterozygous Scn1aWT/R613X mice, with marginal expression in homozygous Scn1aR613X/R613X mice. Together, we introduce a novel Dravet model carrying the R613X Scn1a nonsense mutation that can. be used to study the molecular and neuronal basis of Dravet, as well as the development of new therapies associated with SCN1A nonsense mutations in Dravet.

neuroscience↗

bioRxiv2022

Exogenous Nav1.1 activity in excitatory and inhibitory neurons reverts Dravet syndrome comorbidities when delivered post-symptom onset in mice with Dravet

Dravet syndrome (DS), an intractable childhood epileptic encephalopathy with a high fatality rate, is caused by loss-of-function mutations in one allele of SCN1A, which encodes NaV1.1. In contrast to other epilepsies, pharmaceutical treatment for DS is limited. Here, we demonstrate that viral vector-mediated delivery of a codon-modified SCN1A cDNA improves DS comorbidities in juvenile and adolescent DS mice (Scn1aA1783V/WT). Notably, bilateral vector injections into the hippocampus or thalamus of DS mice improved the survival of the mice, reduced the occurrence of epileptic spikes, provided protection from thermally-induced seizures, and corrected background electrocorticography activity. Together, our results provide a proof-of-concept for the potential of SCN1A delivery as a therapeutic approach for infants and adolescents with DS-associated comorbidities.

neuroscience↗