Inspired by a patient
Vetro A, Pelorosso C, Balestrini S, Masi A, Hambleton S, Argilli E, Conti V, Giubbolini S, Barrick R, Bergant G, Writzl K, Bijlsma EK, Brunet T, Cacheiro P, Mei D, Devlin A, Hoffer MJV, Machol K, Mannaioni G, Sakamoto M, Menezes MP, Courtin T, Sherr E, Parra R, Richardson R, Roscioli T, Scala M, von Stülpnagel C, Smedley D; TMEM63B collaborators; Genomics England Research Consortium; Torella A, Tohyama J, Koichihara R, Hamada K, Ogata K, Suzuki T, Sugie A, van der Smagt JJ, van Gassen K, Valence S, Vittery E, Malone S, Kato M, Matsumoto N, Ratto GM, Guerrini R. Stretch-activated ion channel TMEM63B associates with developmental and epileptic encephalopathies and progressive neurodegeneration. Am J Hum Genet. 2023 Aug 3;110(8):1356-1376. doi: 10.1016/j.ajhg.2023.06.008. Epub 2023 Jul 7. PMID: 37421948; PMCID: PMC10432263.
Abstract
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 Ca2+ 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.
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DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 118; DEE118
- Nystagmus
- Tube-feeding (in some patients)
- Seizures, refractory
- Focal seizures with impaired awareness
- Tonic seizures
- Bilateral tonic-clonic seizures
- Infantile spasms
- Febrile seizures
- Myoclonic seizures
- Status epilepticus (in some patients)
- Global developmental delay, moderate to profound
- Hypotonia
- Spastic quadriparesis
- Inability to walk
- Ataxic gait
- Impaired intellectual development, moderate to profound
- Absent speech (in most patients)
- Background slowing seen on EEG
- Multifocal epileptiform discharges
- Hypsarrhythmia (in some patients)
- Delayed myelination seen on brain imaging
- White matter abnormalities
- Thin corpus callosum
- Enlarged lateral ventricles
- Dysmorphic lateral ventricles
- Cortical atrophy
- Cerebellar atrophy
- Blood transfusions (in some patients)
- Hemolysis
- Most individuals have profound developmental delay
- Progressive disorder
- De novo mutation
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