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

ABSTRACT: Mutations in 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 encodes the mitochondrial transcription elongation factor responsible for enhancing the processivity of mitochondrial RNA polymerase, POLRMT. We report for the first time that TEFM variants are associated with mitochondrial respiratory chain deficiency and a wide range of clinical presentations including mitochondrial myopathy with a treatable neuromuscular transmission defect. Mechanistically, we show muscle and primary fibroblasts from the affected individuals have reduced levels of promoter distal mitochondrial RNA transcripts. Finally, tefm knockdown in zebrafish embryos resulted in neuromuscular junction abnormalities and abnormal mitochondrial function, strengthening the genotype-phenotype correlation. Our study highlights that TEFM regulates mitochondrial transcription elongation and its defect results in variable, tissue-specific neurological and neuromuscular symptoms.

SUBMITTER: Van Haute L

PROVIDER: S-EPMC9950373 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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

Van Haute Lindsey L O'Connor Emily E Díaz-Maldonado Héctor H Munro Benjamin B Polavarapu Kiran K Hock Daniella H DH Arunachal Gautham G Athanasiou-Fragkouli Alkyoni A Bardhan Mainak M Barth Magalie M Bonneau Dominique D Brunetti-Pierri Nicola N Cappuccio Gerarda G Caruana Nikeisha J NJ Dominik Natalia N Goel Himanshu H Helman Guy G Houlden Henry H Lenaers Guy G Mention Karine K Murphy David D Nandeesh Bevinahalli B Olimpio Catarina C Powell Christopher A CA Preethish-Kumar Veeramani V Procaccio Vincent V Rius Rocio R Rebelo-Guiomar Pedro P Simons Cas C Vengalil Seena S Zaki Maha S MS Ziegler Alban A Thorburn David R DR Stroud David A DA Maroofian Reza R Christodoulou John J Gustafsson Claes C Nalini Atchayaram A Lochmüller Hanns H Minczuk Michal M Horvath Rita R

Nature communications 20230223 1

Mutations in 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 encodes the mitochondrial transcription elongation factor responsible for enhancing the processivity of mitochondrial RNA polymerase, POLRMT. We report for the first time that TEFM variants are asso ...[more]

PMID: 36823193

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Project description:Altogether 95 children with primary bone fragility were screened for variants in PLS3, the gene underlying X-linked osteoporosis. Two children with multiple peripheral and spinal fractures and low BMD had novel disease-causing PLS3 variants. Children with milder phenotypes had no pathogenic variants. PLS3 screening is indicated in childhood-onset primary osteoporosis.The study aimed to determine the role of pathogenic PLS3 variants in children's bone fragility and to elucidate the associated phenotypic features.Two cohorts of children with bone fragility were screened for variants in PLS3, the gene underlying X-linked osteoporosis. Cohort I comprised 31 patients with childhood-onset primary osteoporosis of unknown etiology. Cohort II comprised 64 children who had sustained multiple fractures but were otherwise healthy. Clinical and radiological data were reviewed. Peripheral blood DNA was Sanger sequenced for coding exons and flanking intronic regions of PLS3.In two patients of cohort I, where other common genetic causes had been excluded, we identified two novel disease-causing PLS3 variants. Patient 1 was a male with bilateral femoral fractures at 10 years, low BMD (Z-score -4.1; 18 years), and multiple vertebral compression fractures. He had a novel nonsense variant in PLS3. Patient 2 was a girl with multiple long bone and vertebral fractures and low BMD (Z-score -6.6 at 6 years). She had a de novo missense variant in PLS3; whole exome sequencing and array-CGH identified no other genetic causes. Iliac crest bone biopsies confirmed low-turnover osteoporosis in both patients. In cohort II, no pathogenic PLS3 variants were identified in any of the subjects.Two novel disease-causing variants in PLS3 were identified in a boy and a girl with multiple peripheral and spinal fractures and very low BMD while no pathogenic variants were identified in children with less severe skeletal fragility. PLS3 screening is warranted in male and female patients with childhood-onset primary osteoporosis.

Dataset Information

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

Publications

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

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