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

ABSTRACT: 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.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Skin

SUBMITTER: David Stroud  

LAB HEAD: David Stroud

PROVIDER: PXD030427 | Pride | 2022-11-07

REPOSITORIES: Pride