A novel variant of the human mitochondrial DnaJ protein, Tid1, associates with a human disease exhibiting developmental delay and polyneuropathy

Eur J Hum Genet. 2019 Jul;27(7):1072-1080. doi: 10.1038/s41431-019-0358-9. Epub 2019 Feb 15.

Abstract

Here, we describe a single patient from a consanguineous family, who suffers from developmental delay, intellectual disability, hypermetropia, moderate alternating esotropia, unsteady gait, and peripheral polyneuropathy. Brain MRI revealed basal ganglia disease. Exome analysis disclosed a homozygous variant, c.452G>C (p.(Arg151Thr)), in TID1, encoding a mitochondrial J-protein chaperone that is known for its function in assisting the Hsp70 chaperone, mortalin, in mediating the refolding of denatured protein and dissolving protein aggregates. Results from in vitro import assays showed that both wild type and c.452G>C (p.(Arg151Thr)) are efficiently imported into isolated mitochondria. However, the import rate of the c.452G>C (p.(Arg151Thr)) variant was less than that of the wild-type protein. In the second part of this study, we demonstrated, in vitro, that the disaggregation function of the mortalin/Tid1 team is compromised in the TID1 c.452G>C (p.(Arg151Thr)) variant, as its chaperone activity has a level similar to that of the non-functional H→Q HPD domain variant. The results shed light on the essential function played by Tid1 during neuronal development.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Amino Acid Substitution
  • Developmental Disabilities / diagnostic imaging
  • Developmental Disabilities / genetics*
  • Female
  • HSP40 Heat-Shock Proteins / genetics*
  • Humans
  • Mitochondrial Proteins / genetics*
  • Mutation, Missense*
  • Polyneuropathies / diagnostic imaging
  • Polyneuropathies / genetics*

Substances

  • DNAJA3 protein, human
  • HSP40 Heat-Shock Proteins
  • Mitochondrial Proteins