Dominant mutations in ITPR3 cause Charcot-Marie-Tooth disease

Ann Clin Transl Neurol. 2020 Oct;7(10):1962-1972. doi: 10.1002/acn3.51190. Epub 2020 Sep 19.


Objective: ITPR3, encoding inositol 1,4,5-trisphosphate receptor type 3, was previously reported as a potential candidate disease gene for Charcot-Marie-Tooth neuropathy. Here, we present genetic and functional evidence that ITPR3 is a Charcot-Marie-Tooth disease gene.

Methods: Whole-exome sequencing of four affected individuals in an autosomal dominant family and one individual who was the only affected individual in his family was used to identify disease-causing variants. Skin fibroblasts from two individuals of the autosomal dominant family were analyzed functionally by western blotting, quantitative reverse transcription PCR, and Ca2+ imaging.

Results: Affected individuals in the autosomal dominant family had onset of symmetrical neuropathy with demyelinating and secondary axonal features at around age 30, showing signs of gradual progression with severe distal leg weakness and hand involvement in the proband at age 64. Exome sequencing identified a heterozygous ITPR3 p.Val615Met variant segregating with the disease. The individual who was the only affected in his family had disease onset at age 4 with demyelinating neuropathy. His condition was progressive, leading to severe muscle atrophy below knees and atrophy of proximal leg and hand muscles by age 16. Trio exome sequencing identified a de novo ITPR3 variant p.Arg2524Cys. Altered Ca2+ -transients in p.Val615Met patient fibroblasts suggested that the variant has a dominant-negative effect on inositol 1,4,5-trisphosphate receptor type 3 function.

Interpretation: Together with two previously identified variants, our report adds further evidence that ITPR3 is a disease-causing gene for CMT and indicates altered Ca2+ homeostasis in disease pathogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Arthrogryposis / genetics*
  • Charcot-Marie-Tooth Disease / genetics*
  • Charcot-Marie-Tooth Disease / therapy
  • Genes, Recessive / genetics
  • Heterozygote
  • Humans
  • Inositol 1,4,5-Trisphosphate Receptors / genetics*
  • Middle Aged
  • Mutation / genetics*
  • Pedigree
  • Phenotype
  • Young Adult


  • ITPR3 protein, human
  • Inositol 1,4,5-Trisphosphate Receptors

Supplementary concepts

  • Multiple Pterygium Syndrome, Autosomal Dominant

Grant support

This work was funded by French National Agency for Research, ANR, Eranet Neuron III program (Acrobat) grant ; Helsingin ja Uudenmaan Sairaanhoitopiiri grant ; Emil Aaltosen Säätiö grant ; Academy of Finland grants 308642, 312438, and AK1308265; Sigrid Juselius Foundation grant ; Helsingin Yliopisto grant ; Horizon 2020 Framework Programme grant 779295; National Institutes of Health grant UL1TR001873; National Center for Advancing Translational Sciences grant .