ArticleHuman genetics2021
A recessive variant in TFAM causes mtDNA depletion associated with primary ovarian insufficiency, seizures, intellectual disability and hearing loss.
Article in Human genetics, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 27 citations in OpenAlex.
- Comprehensive Insights into Perrault Syndrome: Genetic Diversity and Clinical Implications.Reproductive sciences (Thousand Oaks, Calif.) · 2026Review
- Targeting WWP1 ameliorates osteoarthritis by suppressing KLF15 ubiquitination to restore mtDNA and mitochondrial function.Molecular genetics and genomics : MGG · 2026Article
- Targeting the TFAM-cGAS-STING axis: a mitochondrial-inflammatory link in the pathogenesis and treatment of diabetic kidney disease.International urology and nephrology · 2026Review
- [HeZhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences · 2025Article
- Mitochondrial DNA Replication and Disease: A Historical Perspective on Molecular Insights and Therapeutic Advances.International journal of molecular sciences · 2025Review
- Liver transplantation in a boy with TFAM mutation associated mtDNA depletion syndrome.Orphanet journal of rare diseases · 2024Article
- Novel PNPLA8 variants associated with primary ovarian insufficiency, tremors, cerebellar ataxia and limb weakness: a case report and literature review.Journal of neurology · 2024Review
- New insights on mitochondrial heteroplasmy observed in ovarian diseases.Journal of advanced research · 2024Review
- Genetic insights into the complexity of premature ovarian insufficiency.Reproductive biology and endocrinology : RB&E · 2024Review
- Mechanisms of mitochondrial dysfunction in ovarian aging and potential interventions.Frontiers in endocrinology · 2024Review
- Deficiency of the mitochondrial ribosomal subunit, MRPL50, causes autosomal recessive syndromic premature ovarian insufficiency.Human genetics · 2023Article
- 35 Years of TFAM Research: Old Protein, New Puzzles.Biology · 2023Review
- LARS2 variants can present as premature ovarian insufficiency in the absence of overt hearing loss.European journal of human genetics : EJHG · 2023Article
- Selected Genetic Factors Associated with Primary Ovarian Insufficiency.International journal of molecular sciences · 2023Review
- A novelFrontiers in genetics · 2023Article
- Premature Ovarian Insufficiency in CLPB Deficiency: Transcriptomic, Proteomic and Phenotypic Insights.The Journal of clinical endocrinology and metabolism · 2022Article
- Article
- Mitochondrial Membranes and Mitochondrial Genome: Interactions and Clinical Syndromes.Membranes · 2022Review
- Review
- AKAP1 contributes to impaired mtDNA replication and mitochondrial dysfunction in podocytes of diabetic kidney disease.International journal of biological sciences · 2022Article
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Authors and funding
15 authors at 8 institutions in 6 countries.
Funding
Abstract
Mitochondrial disorders are collectively common, genetically heterogeneous disorders in both pediatric and adult populations. They are caused by molecular defects in oxidative phosphorylation, failure of essential bioenergetic supply to mitochondria, and apoptosis. Here, we present three affected individuals from a consanguineous family of Pakistani origin with variable seizures and intellectual disability. Both females display primary ovarian insufficiency (POI), while the male shows abnormal sex hormone levels. We performed whole exome sequencing and identified a recessive missense variant c.694C > T, p.Arg232Cys in TFAM that segregates with disease. TFAM (mitochondrial transcription factor A) is a component of the mitochondrial replisome machinery that maintains mtDNA transcription and replication. In primary dermal fibroblasts, we show depletion of mtDNA and significantly altered mitochondrial function and morphology. Moreover, we observed reduced nucleoid numbers with significant changes in nucleoid size or shape in fibroblasts from an affected individual compared to controls. We also investigated the effect of tfam impairment in zebrafish; homozygous tfam mutants carrying an in-frame c.141_149 deletion recapitulate the mtDNA depletion and ovarian dysgenesis phenotypes observed in affected humans. Together, our genetic and functional data confirm that TFAM plays a pivotal role in gonad development and expands the repertoire of mitochondrial disease phenotypes.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.