Stretch-activated ion channel TMEM63B associates with developmental and epileptic encephalopathies and progressive neurodegeneration
The American Journal of Human Genetics, ISSN: 0002-9297, Vol: 110, Issue: 8, Page: 1356-1376
2023
- 12Citations
- 46Captures
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Metrics Details
- Citations12
- Citation Indexes12
- CrossRef10
- Captures46
- Readers46
- 46
Article Description
By converting physical forces into electrical signals or triggering intracellular cascades, stretch-activated ion channels allow the cell to respond to osmotic and mechanical stress. Knowledge of the pathophysiological mechanisms underlying associations of stretch-activated ion channels with human disease is limited. Here, we describe 17 unrelated individuals with severe early-onset developmental and epileptic encephalopathy (DEE), intellectual disability, and severe motor and cortical visual impairment associated with progressive neurodegenerative brain changes carrying ten distinct heterozygous variants of TMEM63B, encoding for a highly conserved stretch-activated ion channel. The variants occurred de novo in 16/17 individuals for whom parental DNA was available and either missense, including the recurrent p.Val44Met in 7/17 individuals, or in-frame, all affecting conserved residues located in transmembrane regions of the protein. In 12 individuals, hematological abnormalities co-occurred, such as macrocytosis and hemolysis, requiring blood transfusions in some. We modeled six variants (p.Val44Met, p.Arg433His, p.Thr481Asn, p.Gly580Ser, p.Arg660Thr, and p.Phe697Leu), each affecting a distinct transmembrane domain of the channel, in transfected Neuro2a cells and demonstrated inward leak cation currents across the mutated channel even in isotonic conditions, while the response to hypo-osmotic challenge was impaired, as were the Ca 2+ transients generated under hypo-osmotic stimulation. Ectopic expression of the p.Val44Met and p.Gly580Cys variants in Drosophila resulted in early death. TMEM63B -associated DEE represents a recognizable clinicopathological entity in which altered cation conductivity results in a severe neurological phenotype with progressive brain damage and early-onset epilepsy associated with hematological abnormalities in most individuals.
Bibliographic Details
http://www.sciencedirect.com/science/article/pii/S0002929723002094; http://dx.doi.org/10.1016/j.ajhg.2023.06.008; http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85166700196&origin=inward; http://www.ncbi.nlm.nih.gov/pubmed/37421948; https://linkinghub.elsevier.com/retrieve/pii/S0002929723002094; https://dx.doi.org/10.1016/j.ajhg.2023.06.008
Elsevier BV
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