Impaired activity of CCA-adding enzyme TRNT1 impacts OXPHOS complexes and cellular respiration in SIFD patient-derived fibroblasts.
SIFD (Sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay) is a novel form of congenital sideroblastic anemia associated with B-cell immunodeficiency, periodic fevers, and developmental delay caused by mutations in the CCA-adding enzyme TRNT1, but the precise molecular pathophysiology is not known.



We show that the disease causing mutations in patient-derived fibroblasts do not affect subcellular localization of TRNT1 and show no gross morphological differences when compared to control cells. Analysis of cellular respiration and oxidative phosphorylation (OXPHOS) complexes demonstrates that both basal and maximal respiration rates are decreased in patient cells, which may be attributed to an observed decrease in the abundance of select proteins of the OXPHOS complexes.



Our data provides further insight into cellular pathophysiology of SIFD.
Molecular Biomedicine Program, Children's Hospital of Eastern Ontario Research Institute, 401 Smyth Road, Ottawa, ON, K1H 8L1, Canada.
Urszula
U
Liwak-Muir
Molecular Biomedicine Program, Children's Hospital of Eastern Ontario Research Institute, 401 Smyth Road, Ottawa, ON, K1H 8L1, Canada.
Hapsatou
H
Mamady
Molecular Biomedicine Program, Children's Hospital of Eastern Ontario Research Institute, 401 Smyth Road, Ottawa, ON, K1H 8L1, Canada.|Newborn Screening Ontario, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada.
Turaya
T
Naas
Molecular Biomedicine Program, Children's Hospital of Eastern Ontario Research Institute, 401 Smyth Road, Ottawa, ON, K1H 8L1, Canada.
Quinlan
Q
Wylie
Molecular Biomedicine Program, Children's Hospital of Eastern Ontario Research Institute, 401 Smyth Road, Ottawa, ON, K1H 8L1, Canada.
Skye
S
McBride
Molecular Biomedicine Program, Children's Hospital of Eastern Ontario Research Institute, 401 Smyth Road, Ottawa, ON, K1H 8L1, Canada.|Department of Pediatrics, University of Ottawa, Ottawa, Ontario, K1H 8M5, Canada.
Matthew
M
Lines
Department of Pathology and Laboratory Medicine, Children's Hospital of Eastern Ontario and University of Ottawa, Ottawa, Ontario, Canada.
Jean
J
Michaud
Molecular Biomedicine Program, Children's Hospital of Eastern Ontario Research Institute, 401 Smyth Road, Ottawa, ON, K1H 8L1, Canada.
Stephen D
SD
Baird
Department of Pediatrics, University of Ottawa, Ottawa, Ontario, K1H 8M5, Canada. pchakraborty@cheo.on.ca.|Newborn Screening Ontario, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada. pchakraborty@cheo.on.ca.
Pranesh K
PK
Chakraborty
Molecular Biomedicine Program, Children's Hospital of Eastern Ontario Research Institute, 401 Smyth Road, Ottawa, ON, K1H 8L1, Canada.|Department of Pediatrics, University of Ottawa, Ottawa, Ontario, K1H 8M5, Canada.
Martin
M
Holcik
D000756:Anemia, Sideroblastic / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D019069:Cell Respiration / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D006801:Humans; D053078:Membrane Potential, Mitochondrial; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000378:metabolism; D009154:Mutation; D009713:Nucleotidyltransferases / Q000235:genetics / Q000378:metabolism*; D010085:Oxidative Phosphorylation
D009713:Nucleotidyltransferases; C000610948:TRNT1 protein, human
Mitochondria; OXPHOS; SIFD; TRNT1; Translation