Mutations in TFAM, encoding mitochondrial transcription factor A, cause neonatal liver failure associated with mtDNA depletion

• Published in: Molecular genetics and metabolism Vol. 119; no. 1-2; pp. 91 - 99
• Main Authors: Stiles, Ashlee R., Simon, Mariella T., Stover, Alexander, Eftekharian, Shaya, Khanlou, Negar, Wang, Hanlin L., Magaki, Shino, Lee, Hane, Partynski, Kate, Dorrani, Nagmeh, Chang, Richard, Martinez-Agosto, Julian A., Abdenur, Jose E.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2016
• Subjects: Animals; DNA Replication - genetics; DNA, Mitochondrial - genetics; DNA, Mitochondrial - metabolism; DNA-Binding Proteins - genetics; Female; Homozygote; Humans; Infant, Newborn; Liver - metabolism; Liver - physiopathology; Liver failure; Liver Failure - genetics; Liver Failure - physiopathology; Male; Mice; Mice, Knockout; Mitochondrial disease; Mitochondrial Diseases - genetics; Mitochondrial Diseases - physiopathology; Mitochondrial Proteins - genetics; mtDNA depletion syndrome; Mutation, Missense; Neonatal Screening; Newborn screening; TFAM mutation; Transcription Factors - genetics; Whole Exome Sequencing; Newborn screening; Liver failure; TFAM mutation; mtDNA depletion syndrome; Mitochondrial disease
• ISSN: 1096-7192; 1096-7206
• DOI: 10.1016/j.ymgme.2016.07.001

In humans, mitochondrial DNA (mtDNA) depletion syndromes are a group of genetically and clinically heterogeneous autosomal recessive disorders that arise as a consequence of defects in mtDNA replication or nucleotide synthesis. Clinical manifestations are variable and include myopathic, encephalomyopathic, neurogastrointestinal or hepatocerebral phenotypes. Through clinical exome sequencing, we identified a homozygous missense variant (c.533C>T; p.Pro178Leu) in mitochondrial transcription factor A (TFAM) segregating in a consanguineous kindred of Colombian–Basque descent in which two siblings presented with IUGR, elevated transaminases, conjugated hyperbilirubinemia and hypoglycemia with progression to liver failure and death in early infancy. Results of the liver biopsy in the proband revealed cirrhosis, micro- and macrovesicular steatosis, cholestasis and mitochondrial pleomorphism. Electron microscopy of muscle revealed abnormal mitochondrial morphology and distribution while enzyme histochemistry was underwhelming. Electron transport chain testing in muscle showed increased citrate synthase activity suggesting mitochondrial proliferation, while respiratory chain activities were at the lower end of normal. mtDNA content was reduced in liver and muscle (11% and 21% of normal controls respectively). While Tfam mRNA expression was upregulated in primary fibroblasts, Tfam protein level was significantly reduced. Furthermore, functional investigations of the mitochondria revealed reduced basal respiration and spare respiratory capacity, decreased mtDNA copy number and markedly reduced nucleoids. TFAM is essential for transcription, replication and packaging of mtDNA into nucleoids. Tfam knockout mice display embryonic lethality secondary to severe mtDNA depletion. In this report, for the first time, we associate a homozygous variant in TFAM with a novel mtDNA depletion syndrome. •Two siblings with TFAM deficiency, a novel hepatocerebral mtDNA depletion syndrome•Major manifestations were IUGR, hypoglycemia and rapidly progressive liver failure.•Both patients had abnormal newborn screening with elevated methionine or tyrosine.•Exome sequencing uncovered a homozygous variant in TFAM in affected siblings.•Tissue studies show mtDNA depletion, decreased nucleoids and TFAM protein expression.