title: Mutations in TFAM, encoding mitochondrial transcription factor A, cause neonatal liver failure associated with mtDNA depletion.
abstract: 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.
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California Los Angeles, CA 90095, USA; UCLA Clinical Genomics Center, Los Angeles, CA 90095, USA.
authors.forename: Ashlee R
authors.initials: AR
authors.lastname: Stiles
authors.affiliation: Division of Metabolic Disorders, CHOC Children's, Orange, CA 92868, USA; Department of Developmental and Cellular Biology, School of Biological Sciences, University of California Irvine, Irvine, CA 92697, USA.
authors.forename: Mariella T
authors.initials: MT
authors.lastname: Simon
authors.affiliation: Division of Metabolic Disorders, CHOC Children's, Orange, CA 92868, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Stover
authors.affiliation: Division of Metabolic Disorders, CHOC Children's, Orange, CA 92868, USA.
authors.forename: Shaya
authors.initials: S
authors.lastname: Eftekharian
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California Los Angeles, CA 90095, USA.
authors.forename: Negar
authors.initials: N
authors.lastname: Khanlou
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California Los Angeles, CA 90095, USA.
authors.forename: Hanlin L
authors.initials: HL
authors.lastname: Wang
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California Los Angeles, CA 90095, USA.
authors.forename: Shino
authors.initials: S
authors.lastname: Magaki
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California Los Angeles, CA 90095, USA; UCLA Clinical Genomics Center, Los Angeles, CA 90095, USA.
authors.forename: Hane
authors.initials: H
authors.lastname: Lee
authors.affiliation: Division of Metabolic Disorders, CHOC Children's, Orange, CA 92868, USA.
authors.forename: Kate
authors.initials: K
authors.lastname: Partynski
authors.affiliation: Department of Pediatrics, David Geffen School of Medicine at University of California Los Angeles, CA 90095, USA.
authors.forename: Nagmeh
authors.initials: N
authors.lastname: Dorrani
authors.affiliation: Division of Metabolic Disorders, CHOC Children's, Orange, CA 92868, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Chang
authors.affiliation: UCLA Clinical Genomics Center, Los Angeles, CA 90095, USA; Department of Pediatrics, David Geffen School of Medicine at University of California Los Angeles, CA 90095, USA; Department of Human Genetics, David Geffen School of Medicine at University of California Los Angeles, CA 90095, USA.
authors.forename: Julian A
authors.initials: JA
authors.lastname: Martinez-Agosto
authors.affiliation: Division of Metabolic Disorders, CHOC Children's, Orange, CA 92868, USA; Department of Pediatrics, University of California Irvine, Orange, CA 92868, USA. Electronic address: jabdenur@choc.org.
authors.forename: Jose E
authors.initials: JE
authors.lastname: Abdenur
mesh_terms: D000818:Animals; D004261:DNA Replication / Q000235:genetics; D004272:DNA, Mitochondrial / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D006720:Homozygote; D006801:Humans; D007231:Infant, Newborn; D008099:Liver / Q000378:metabolism / Q000503:physiopathology; D017093:Liver Failure / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D028361:Mitochondrial Diseases / Q000235:genetics* / Q000503:physiopathology; D024101:Mitochondrial Proteins / Q000235:genetics*; D020125:Mutation, Missense; D015997:Neonatal Screening; D014157:Transcription Factors / Q000235:genetics*; D000073359:Exome Sequencing
chemical_list: D004272:DNA, Mitochondrial; D004268:DNA-Binding Proteins; D024101:Mitochondrial Proteins; C499631:TFAM protein, human; D014157:Transcription Factors
keywords: Liver failure; Mitochondrial disease; Newborn screening; TFAM mutation; mtDNA depletion syndrome