The vacuolar H-ATPase is a multisubunit enzyme which plays an essential role in the acidification and functions of lysosomes, endosomes, and synaptic vesicles. Many genes encoding subunits of V-ATPases, namely and , have been associated with neurodevelopmental disorders and epilepsy. The autosomal dominant p.Arg506* variant can cause both congenital deafness with onychodystrophy, autosomal dominant (DDOD) and deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures syndromes (DOORS). Some but not all individuals with this truncating variant have intellectual disability and/or epilepsy, suggesting incomplete penetrance and/or variable expressivity. To further explore the impact of the p.Arg506* variant in neurodevelopment and epilepsy, we generated mutant mice and performed standardized phenotyping using the International Mouse Phenotyping Consortium (IMPC) pipeline. In addition, we assessed the EEG profile and seizure susceptibility of mice. Behavioral tests revealed that the mice present locomotor hyperactivity and show less anxiety-associated behaviors. Moreover, EEG analyses indicate that mutant mice have interictal epileptic activity and that both heterozygous (like patients) and homozygous mice have reduced seizure thresholds to pentylenetetrazol. Our results confirm that variants in can cause seizures and that the heterozygous mouse model is a valuable tool to further explore the pathophysiology and potential treatments for vacuolar ATPases-associated epilepsy and disorders.
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http://dx.doi.org/10.3390/genes14081538 | DOI Listing |
Clin Genet
January 2025
NHC Key Laboratory of Human Stem Cell and Reproductive Engineering, School of Basic Medical Sciences, Central South University, ChangSha, China.
An increasing number of patients utilizing in vitro fertilization (IVF) and assisted reproductive technology (ART) are characterized as impaired or poor ovarian responders (PORs). Owing to its unclear molecular etiology, the management of patients with age-related ovarian characteristics remains a controversial and complex clinical concern. Therefore, it is important to identify and understand the etiological causes behind POR to develop more effective and efficient management strategies for these patients.
View Article and Find Full Text PDFMuscle Nerve
January 2025
Department of Anatomy, Federal University of Alfenas (UNIFAL-MG), Alfenas, Brazil.
Introduction/aims: Duchenne muscular dystrophy (DMD) is caused by pathogenic variants in the DMD gene, making muscle fibers susceptible to contraction-induced membrane damage. Given the potential beneficial action of cannabidiol (CBD), we evaluated the in vitro effect of full-spectrum CBD oil on the viability of dystrophic muscle fibers and the in vivo effect on myopathy of the mdx mouse, a DMD model.
Methods: In vitro, dystrophic cells from the mdx mouse were treated with full-spectrum CBD oil and assessed with cell viability and cytotoxic analyses.
Adv Sci (Weinh)
January 2025
State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China.
Biomolecular condensates segregate nuclei into discrete regions, facilitating the execution of distinct biological functions. Here, it is identified that the WW domain containing adaptor with coiled-coil (WAC) is localized to nuclear speckles via its WW domain and plays a pivotal role in regulating alternative splicing through the formation of biomolecular condensates via its C-terminal coiled-coil (CC) domain. WAC acts as a scaffold protein and facilitates the integration of RNA-binding motif 12 (RBM12) into nuclear speckles, where RBM12 potentially interacts with the spliceosomal U5 small nuclear ribonucleoprotein (snRNP).
View Article and Find Full Text PDFCirc Res
January 2025
Hypertension Research Laboratory, School of Biological Sciences (R.R.M., T.Z., E.D., L.X., A.B.-W., H.A.J., M.N., M.P., K.C.L., W.Q., J.A.O.D., F.Z.M.).
Background: Fermentation of dietary fiber by the gut microbiota leads to the production of metabolites called short-chain fatty acids, which lower blood pressure and exert cardioprotective effects. Short-chain fatty acids activate host signaling responses via the functionally redundant receptors GPR41 and GPR43, which are highly expressed by immune cells. Whether and how these receptors protect against hypertension or mediate the cardioprotective effects of dietary fiber remains unknown.
View Article and Find Full Text PDFAm J Med Genet A
January 2025
Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
Primary Hypertrophic Osteoarthropathy (PHOAR1) is characterized by autosomal recessive loss of function variants in 15-hydroxyprostaglandin dehydrogenase (HPGD) leading to digital clubbing, periostosis, pachydermia, and severe hyperhidrosis. HPGD catalyzes the first step of prostaglandin E2 (PGE2) degradation. Selective COX-2 inhibitors have proved beneficial in adults, though it is unknown if early initiation of COX-2 inhibitors can alter the natural history of PHOAR1.
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