611. Dnmt1 Complex Disorders: Neurodegeneration From a Specific Dna Methylation Defect. the Mutation Knock in Mouse Model Present Similar to Clinical Form of Hsan1e
Year: 2025
Type: conference-abstract
Abstract: Background DNA methyltransferase 1 (DNMT1) is essential for DNA methylation and chromatin stability. DNMT1 on chromosome 19p 13.2 mutations in this gene lead to a dominantly inherited neurodegenerative phenotype with a triad of symptoms shared by all patients that includes: 1) Peripherally sensory neuropathy; 2) Sensorineural hearing loss; 3) Early on set dementia. Some patients also have seizure, narcolepsy, cerebellar ataxia, optic nerve atrophy. Importantly, almost phenotype mutations patients are can grow up until adulthood, symptoms begin at middle aged, and death typically occurs around age of 50 years. The initial clinical terms Hereditary Sensory and Autonomic Neuropathy type 1 E (HSAN1E: OMIM-614116). Aims & Objectives In DNMT1 mutations t he mutation in p.Tyr495 changing to cystaine (Y495C), the first discovard and common mutation of hereditary sensory neuropathy 1E, we producted the mutation knock-in mouse model of Y495C, verify the effect on homozygous and heterozygous mutant mice. To invastigate of impact phenotype changing the landscape of gene expression, compair wild -type littermate and tne mutant mouse. Method By using Gene knockin technichs, the process of tardeted insertion of the exogenous gene (Dnmt1 TAT>TGT) at a specific locus (Exon 19) in genomic Dnmt1, generate homozygous and heterozygouse mutant mouse. Experimental Design: To compair with wild-type littermate with mutant mouse model, parformed Rotor rod test as a neurophysiology and Nerve conduction study as a sensory test. Neuropathologically, we also parformed sciatic notch light microscopy epoxy-embedded methyl bluestained nerve. Results DNMT1 mutation knock in mouse model; Homozygous Y495C/Y495C mice were small and immatureness copaired to wt/Y495C heterozygpus one, were lethal 9.5 days during gestation. On the other hand heterozygous wt/Y495C mutant mouse catch up, give birth and grew up normally. At 9 month old Y495C mice, their sciatic notch light microscopy epoxy-embedded methyl bluestained nerve showed the characteristic fiber loss and axional degeneration. At 10-12 months and 16-18 months old, in nerve conduction study and Rotor-Rod testing, wt/Y495C mice decreased SNAP-Amplitude reduced, total running time of Rotor-Rod test dicreased with their ages. Discussion & Conclusions Heterozygous mutation in DNA metyrtransferase 1 (DNMT1) Y495C mice presented normal neural development and lifespan as well as the disease of human being (HSAN1E). Around 30's age, the patient's sensory loss become clearly present periferal sensory neuropathy. The gait disturbance is also gradually advanced with ataxia. Axonal degeneration at 9 month, deteriorating sensorimotor coordination manifested with age by Rotor-Rod test. Dementing status of DNMT1E shows FTD like symptons which advanced prominent around 40's. Reducing total ranning time by Rotre-Rod test may means loss of urge and attetion as a frontal lobe sign. Y495C homozygous mutant mice die during gestation. Homozygous genome methyration reduction cause newral hypogenesis of the fetus. The mutation in p.Tyr495 changing to cystaine (Y495C) are located in the middle part of TS domain which is hot spot mutant site, where a highly-conserved region has been identified essential for the binding of heterochromatin.
Authors: K Hojo, C J Klein, H Yamanishi
Institution: Mayo Clinic
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,693
OpenAlex ID: W4413284704