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TEFM variants impair mitochondrial transcription elongation causing childhood-onset neurological disease

ABSTRACT: TEFM variants impair mitochondrial transcription elongation causing childhood-onset neurological disease

PROVIDER: PRJNA768394 | ENA |

REPOSITORIES: ENA

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TEFM variants impair mitochondrial transcription elongation causing childhood-onset neurological disease

Project description:Mutations in either the mitochondrial or nuclear genomes are associated with a diverse group of human disorders characterized by impaired mitochondrial respiration. Within this group, an increasing number of mutations have been identified in nuclear genes involved in mitochondrial RNA biology. The TEFM gene codes for the mitochondrial transcription elongation factor responsible for enhancing the processivity of mitochondrial RNA polymerase, POLRMT. Here, we report for the first time that TEFM variants are associated with mitochondrial respiratory chain deficiency and a wide range of clinical presentations including neonatal lactic acidosis, epileptic encephalopathy, developmental delay, intellectual disability or mitochondrial myopathy with a treatable neuromuscular transmission defect. Mechanistically, we show that muscle samples and primary fibroblasts from the affected individuals have reduced levels of promoter distal mitochondrial RNA transcripts, consistent with decreased processivity of POLRMT when TEFM is dysfunctional. We provide further evidence for the pathogenicity of these variants by investigating mitochondrial transcription and proteomic changes in patient cells and muscle and by studying TEFM activity in an in vitro system. Finally, tefm knock-down in zebrafish embryos resulted in neuromuscular junction abnormalities and abnormal mitochondrial function, strengthening the genotype-phenotype correlation. In conclusion, our study highlights that TEFM regulates mitochondrial transcription elongation in human tissues and its defect results in variable, tissue specific neurological and neuromuscular symptoms.

2022-11-07 | PXD030427 | Pride

TEFM variants impair mitochondrial transcription elongation causing childhood-onset neurological disease

Project description:We report that TEFM variants are associated with mitochondrial respiratory chain deficiency. We show that patient's cells have reduced levels of promoter distal mitochondrial RNA transcripts.

2022-11-08 | GSE185245 | GEO

Next Generation Sequencing Approaches to Childhood Neurological Diseases

Project description:Next Generation Sequencing Approaches to Childhood Neurological Diseases

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AGO2 mutations impair RNA interference and human neurological development

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Pathogenic PDE12 variants impair mitochondrial RNA processing causing neonatal-onset mitochondrial disease

Project description:The PDE12 gene codes for the poly(A)-specific exoribonuclease, involved in the quality control of mitochondrial non-coding RNAs. Here, we report that disease-causing PDE12 variants in three unrelated families are associated with mitochondrial respiratory chain deficiencies. Clinically, they presented in utero and within the neonatal period with muscle and brain involvement leading to marked cytochrome c oxidase (COX) deficiency in muscle and severe lactic acidosis. To analyze perturbations in specific cellular pathways contributing to pathogenesis in our patient cohort, we used Affymetrix Clariom D transcriptome arrays to study the RNA levels in fibroblasts derived from two patient (Patient 2 and patient 3), comparing these to age-matched controls.

2024-09-29 | E-MTAB-14251 | biostudies-arrayexpress

POLRMT mutations impair mitochondrial transcription causing neurological disease.

Project description:While >300 disease-causing variants have been identified in the mitochondrial DNA (mtDNA) polymerase γ, no mitochondrial phenotypes have been associated with POLRMT, the RNA polymerase responsible for transcription of the mitochondrial genome. Here, we characterise the clinical and molecular nature of POLRMT variants in eight individuals from seven unrelated families. Patients present with global developmental delay, hypotonia, short stature, and speech/intellectual disability in childhood; one subject displayed an indolent progressive external ophthalmoplegia phenotype. Massive parallel sequencing of all subjects identifies recessive and dominant variants in the POLRMT gene. Patient fibroblasts have a defect in mitochondrial mRNA synthesis, but no mtDNA deletions or copy number abnormalities. The in vitro characterisation of the recombinant POLRMT mutants reveals variable, but deleterious effects on mitochondrial transcription. Together, our in vivo and in vitro functional studies of POLRMT variants establish defective mitochondrial transcription as an important disease mechanism.

| S-EPMC7893070 | biostudies-literature

Identifying autosomal recessive mutations causing neurological disorders

Project description:The objective of this study is to resequence of targeted intervals containing autosomal recessive variants causing neurological disorders in consanguineous pedigrees. Using homozygosity mapping, three intervals of very different sizes have previously been unambiguously mapped for three different neurological diseases: 2.4Mb, 8Mb and 14.3Mb in size, for Microlissencephaly, Severe Mental Retardation and Complicated hereditary spastic paraplegia respectively. This study is a pilot to assess how well custom targeted resequencing performs across a broad size range of intervals. The study design is to use a different custom capture probe set for each interval, pulldown from a single patient from each family, and sequence 1 lane using Illumina paired-reads for each sample. Candidate variants will be followed up in the families themselves, and in patients with similar phenotypes from outbred populations.

| EGAS00001000023 | EGA

Gene expression profiles of fibroblasts from childhood cerebral adrenoleukodystrophy patients and healthy controls

2012-03-01 | GSE34308 | GEO

Childhood medulloblastoma

Project description:Childhood medulloblastoma

| PRJNA656544 | ENA

Gene expression profiles of fibroblasts from childhood cerebral adrenoleukodystrophy patients and healthy controls

Project description:Although not an affected cell type, skin fibroblasts from individuals with childhood cerebral adrenoleukodystrophy (CCALD), an early onset X-linked neurological disorder, show defects in very long chain fatty acid (VLCFA) metabolism that provide the basis for clinical diagnostic tests. We report the gene expression profiles of fibroblasts from childhood cerebral adrenoleukodystrophy patients and healthy controls Primary dermal fibroblast cultures from 5 CC-ALD patients and 5 healthy controls were cultured in DMEM medium supplemented with 10% FBS at 37°C with 5% CO2 until confluence for RNA extraction. The overall goal was to identify genes that are differentially expressed between CCALD patients and healthy controls

2012-03-01 | E-GEOD-34308 | biostudies-arrayexpress

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