A recessive variant in TFAM causes mtDNA depletion associated with primary ovarian insufficiency, seizures, intellectual disability and hearing loss

Farid Ullah, Waqar Rauf, Kamal Khan, Sheraz Khan, Katrina M. Bell, Vanessa Cristina de Oliveira, Muhammad Tariq, Shabnam Bakhshalizadeh, Philippe Touraine, Elias Nicholas Katsanis, Andrew Sinclair, Sijie He, Elena J. Tucker, Shahid M. Baig, Erica E. Davis*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1733-1751
Number of pages19
JournalHuman Genetics
Volume140
Issue number12
DOIs
StatePublished - Dec 2021

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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