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. Epub 2020 Jan 30.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Amino Acid Sequence
  • Cataract / etiology*
  • Cataract / pathology
  • Cerebellum / abnormalities*
  • Cerebellum / pathology
  • Child, Preschool
  • Developmental Disabilities / etiology*
  • Developmental Disabilities / pathology
  • Female
  • Homozygote
  • Humans
  • Infant
  • Male
  • Mutation*
  • Nervous System Malformations / etiology*
  • Nervous System Malformations / pathology
  • Pedigree
  • Phenotype
  • Phosphorus-Oxygen Lyases / genetics*
  • Phosphorylation
  • Phosphotransferases (Alcohol Group Acceptor) / genetics*
  • Sequence Homology
  • Whole Exome Sequencing

Substances

  • Phosphotransferases (Alcohol Group Acceptor)
  • triokinase
  • Phosphorus-Oxygen Lyases
  • FMN cyclase

Supplementary concepts

  • Cerebellar Hypoplasia