2. Academic Validation
  3. Bi-allelic Variants in TKFC Encoding Triokinase/FMN Cyclase Are Associated with Cataracts and Multisystem Disease

Bi-allelic Variants in TKFC Encoding Triokinase/FMN Cyclase Are Associated with Cataracts and Multisystem Disease

  • Am J Hum Genet. 2020 Feb 6;106(2):256-263. doi: 10.1016/j.ajhg.2020.01.005.
Saskia B Wortmann 1,  Brigitte Meunier 2,  Lamia Mestek-Boukhibar 3,  Florence van den Broek 4,  Elaina M Maldonado 5,  Emma Clement 6,  Daniel Weghuber 4,  Johannes Spenger 4,  Zdenek Jaros 7,  Fatma Taha 5,  Wyatt W Yue 8,  Simon J Heales 9,  James E Davison 10,  Johannes A Mayr 4,  Shamima Rahman 11
Affiliations

Affiliations

  • 1 University Children's Hospital, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU), 5020 Salzburg, Austria; Institute of Human Genetics, Technical University München, 81675 Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum, 85764 Neuherberg, Germany.
  • 2 Université Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC), 91198 Gif-sur-Yvette, France.
  • 3 GOSgene Centre for Translational Omics and NIHR GOSH Biomedical Research Centre, UCL Great Ormond Street Institute of Child Health, London WC1N 1EH, UK.
  • 4 University Children's Hospital, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU), 5020 Salzburg, Austria.
  • 5 Mitochondrial Research Group, UCL Great Ormond Street Institute of Child Health, London WC1N 1EH, UK.
  • 6 Department of Clinical Genetics, North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, UK.
  • 7 Department of Pediatrics, Landesklinikum Zwettl, 3910 Zwettl, Austria.
  • 8 Structural Genomics Consortium, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7DQ, UK.
  • 9 Mitochondrial Research Group, UCL Great Ormond Street Institute of Child Health, London WC1N 1EH, UK; Neurometabolic Unit, National Hospital for Neurology, Queen Square, London WC1N 3BG, UK; Department of Chemical Pathology, Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK.
  • 10 Metabolic Unit, Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK.
  • 11 Mitochondrial Research Group, UCL Great Ormond Street Institute of Child Health, London WC1N 1EH, UK; Metabolic Unit, Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK. Electronic address: shamima.rahman@ucl.ac.uk.
PMID: 32004446 DOI: 10.1016/j.ajhg.2020.01.005
Abstract

We report an inborn error of metabolism caused by TKFC deficiency in two unrelated families. Rapid trio genome Sequencing in family 1 and exome Sequencing in family 2 excluded known genetic etiologies, and further variant analysis identified rare homozygous variants in TKFC. TKFC encodes a bifunctional Enzyme involved in fructose metabolism through its glyceraldehyde kinase activity and in the generation of riboflavin cyclic 4',5'-phosphate (cyclic FMN) through an FMN lyase domain. The TKFC homozygous variants reported here are located within the FMN lyase domain. Functional assays in yeast support the deleterious effect of these variants on protein function. Shared phenotypes between affected individuals with TKFC deficiency include cataracts and developmental delay, associated with cerebellar hypoplasia in one case. Further complications observed in two affected individuals included liver dysfunction and microcytic anemia, while one had fatal cardiomyopathy with lactic acidosis following a febrile illness. We postulate that deficiency of TKFC causes disruption of endogenous fructose metabolism leading to generation of by-products that can cause cataract. In line with this, an affected individual had mildly elevated urinary galactitol, which has been linked to cataract development in the galactosemias. Further, in light of a previously reported role of TKFC in regulating innate Antiviral immunity through suppression of MDA5, we speculate that deficiency of TKFC leads to impaired innate immunity in response to viral illness, which may explain the fatal illness observed in the most severely affected individual.

Keywords

TKFC; cardiomyopathy; cataracts; cyclic FMN; developmental delay; fructose metabolism; inborn error of metabolism; innate immunity; rapid genome sequencing; triokinase.

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