TMEM63C mutations cause mitochondrial morphology defects and underlie hereditary spastic paraplegia

Tábara, Luis Carlos; Al-Salmi, Fatema; Maroofian, Reza; Futaisi, Amna Al; Al-Murshedi, Fathiya; Kennedy, Joanna; Day, Jacob; Courtin, Thomas; Al-Khayat, Aisha; Galedari, Hamid; Mazaheri, Neda; Protasoni, Margherita; Johnson, Mark A.; Leslie, Joseph S; Salter, Claire; Rawlins, Lettie E; Fasham, James; Al‐Maawali, Almundher; Voutsina, Nikol; Charles, Perrine; Harrold, Laura; Keren, Boris; Kunji, Edmund R. S.; Vona, Barbara; Jelodar, Gholamreza; Sedaghat, Alireza; Shariati, Gholamreza; Houlden, Henry; Crosby, Andrew H.; Prudent, Julien; Baple, Emma L.

doi:10.1093/brain/awac123

Cited by 21 publications

(15 citation statements)

References 59 publications

(65 reference statements)

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“…MYO16 (33), HS3ST4 (34), SORCS3 (35)), metabolism ( GCK (36)), neuronal survival, dendrite branching, axonal growth and neural projection in development (e.g. NSG1 (37), TMEM3C6 (38), TMOD1 (39), PLPPR4 (40), NEBL (41), NRN1 (42) and GFRA2 (43)) and channelopathies (e.g. CACNA1B/C (44), SCN3A (45)) ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Multi-omics approach reveals dysregulated genes during hESCs neuronal differentiation exposure to paracetamol

Spildrejorde

Samara

Sharma

et al. 2022

Preprint

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Background: Several epidemiological studies have found associations between long-term prenatal exposure to paracetamol and neurodevelopmental outcomes in childhood. Pharmacoepigenetic studies have identified differences in DNA methylation (DNAm) in cord blood between exposed and unexposed neonates. However, the causal implications and impact of prenatal long-term paracetamol exposure on brain development are not known. Methods: We exposed human embryonic stem cells (hESCs) undergoing in vitro neuronal differentiation to daily changes of media containing amount of paracetamol corresponding to human foetal exposure with maternal therapeutic doses. An integrated multi-omics approach was used to investigate epigenetic and transcriptomic effects of paracetamol on the early stages of human brain development. Results: Multi-omics analyses of DNAm, chromatin opening, and gene expression identified dose-dependent effects on cell proliferation and maturation. We found differentially methylated and/or expressed genes involved in signal transduction, neurotransmitter secretion and cell fate determination trajectories. Integration of single-cell RNA-seq and ATAC-seq showed that paracetamol-induced changes in chromatin opening were linked to transcription. For example, EP300 encoding a histone acetyltransferase and H3K27ac were linked to many putative cis regulatory elements and downregulated upon paracetamol exposure. Some of the genes are involved in neuronal injury, response to toxic insults and development-specific pathways, such as KCNE3, overlapped with differentially methylated genes previously identified in cord blood associated with prenatal paracetamol exposure. Conclusion: We identified dose-dependent epigenetic and transcriptional changes in hESCs undergoing neuronal differentiation after paracetamol exposure. The overlap of differentially methylated genes with our previous analysis in cord blood from children exposed to paracetamol during pregnancy could suggest a causal role in impaired neurodevelopment.

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Section: Resultsmentioning

confidence: 99%

Multi-omics approach reveals dysregulated genes during hESCs neuronal differentiation exposure to paracetamol

Spildrejorde

Samara

Sharma

et al. 2022

Preprint

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“…More than 87 genes or gene loci (SPG) were described as causing HSP subtypes, 2,3 presenting with autosomal dominant (AD), autosomal recessive (AR), mitochondrial or X‐linked inheritance patterns. SPG4, caused by pathogenic variants in SPAST (2p22.3), is the most frequent HSP subtype, representing up to 60% of families with clear AD inheritance 4,5 .…”

Section: Introductionmentioning

confidence: 99%

“…1,2 Pathogenic variants in genes related to axonal transport, membrane and organelle trafficking, mitochondrial dysfunction and lipid metabolism are the main mechanisms associated with these diseases' development. 2 More than 87 genes or gene loci (SPG) were described as causing HSP subtypes, 2,3 presenting with autosomal dominant (AD), autosomal recessive (AR), mitochondrial or X-linked inheritance patterns. SPG4, caused by pathogenic variants in SPAST (2p22.3), is the most frequent HSP subtype, representing up to 60% of families with clear AD inheritance.…”

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confidence: 99%

Copy number variations in SPAST and ATL1 are rare among Brazilians

Fussiger,

Pereira,

Padilha

et al. 2023

Clinical Genetics

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Copy number variations (CNV) may represent a significant proportion of SPG4 and SPG3A diagnosis, the most frequent autosomal dominant subtypes of hereditary spastic paraplegias (HSP). We aimed to assess the frequency of CNVs in SPAST and ATL1 and to update the molecular epidemiology of HSP families in southern Brazil. A cohort study that included 95 Brazilian index cases with clinical suspicion of HSP was conducted between April 2011 and September 2022. Multiplex Ligation Dependent Probe Amplification (MLPA) was performed in 41 cases without defined diagnosis by different massive parallel sequencing techniques (MPS). Diagnosis was obtained in 57/95 (60%) index cases, 15/57 (26.3%) being SPG4. Most frequent autosomal recessive HSP subtypes were SPG7 followed by SPG11, SPG76 and cerebrotendinous xanthomatosis. No CNVs in SPAST and ATL1 were found. Copy number variations are rare among SPG4 and SPG3A families in Brazil. Considering the possibility of CNVs detection by specific algorithms with MPS data, we consider that thisis likely the most cost-effective approach to investigate CNVs in these genes in lowrisk populations, with MLPA being reserved as an orthogonal confirmatory test.

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“…Other members of the TMEM63 family have been associated with monogenic disorders, namely "transient infantile hypomyelinating leukodystrophy-19 (HLD19)" (MIM #618688), with developmental delay of variable severity, caused by heterozygous TMEM63A variants (6)(7)(8), and "autosomal recessive spastic paraplegia-87 (SPC-87)" (MIM #619966), caused by biallelic truncating variants of TMEM63C (9). The TMEM63B gene still lacks a clear association with human diseases, and it is not yet listed either in the OMIM's Morbid Map of the Human Genome or in the ClinGen Gene-Disease Validity database (https://www.clinicalgenome.org/).…”

Section: Introductionmentioning

confidence: 99%

Stretch-activated ion channel TMEM63B associates with developmental and epileptic encephalopathies and progressive neurodegeneration

Vetro

Balestrini

Pelorosso

et al. 2022

Preprint

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By converting physical forces into electrical signals or triggering intracellular cascades, stretch-activated ion channels (SACs) allow the cell to respond to osmotic and mechanical stress. Knowledge of the pathophysiological mechanisms underlying associations of SACs with human disease is limited. Here we describe 16 unrelated patients, 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 de novo variants of TMEM63B. Variants were missense, including the recurrent V44M in 7/16 patients, or in-frame, and affected highly conserved residues located in transmembrane regions of the protein. In 12 patients, haematological abnormalities co-occurred, such as macrocytosis and haemolysis, requiring blood transfusions in some. We modelled V44M, R443H, and T481N in transfected Neuro2a cells and demonstrated leak inward 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 V44M and G580C variants in Drosophila resulted in early death. TMEM63B-associated DEE represents a novel clinicopathological entity in which altered cation conductivity results in a severe neurological phenotype with progressive brain damage and early onset epilepsy, associated with haematological abnormalities in most patients.

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TMEM63C mutations cause mitochondrial morphology defects and underlie hereditary spastic paraplegia

Cited by 21 publications

References 59 publications

Multi-omics approach reveals dysregulated genes during hESCs neuronal differentiation exposure to paracetamol

Multi-omics approach reveals dysregulated genes during hESCs neuronal differentiation exposure to paracetamol

Copy number variations in SPAST and ATL1 are rare among Brazilians

Stretch-activated ion channel TMEM63B associates with developmental and epileptic encephalopathies and progressive neurodegeneration

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