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Related Experiment Video

Updated: Jun 22, 2025

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A recurrent missense variant in ITPR3 causes demyelinating Charcot-Marie-Tooth with variable severity.

Danique Beijer1,2, Maike F Dohrn1,3, Adriana Rebelo1

  • 1Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL 33136, USA.

Brain : a Journal of Neurology
|June 28, 2024
PubMed
Summary

A new Charcot-Marie-Tooth (CMT) gene, ITPR3, was identified through genetic sequencing. A specific mutation, p.Thr1424Met, was found in multiple families, causing CMT type 1 with variable symptoms.

Keywords:
demyelinating Charcot-Marie-Tooth diseaseinositol 1,4,5-trisphosphatenext-generation sequencing

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Area of Science:

  • Genetics
  • Neurology
  • Molecular Biology

Background:

  • Charcot-Marie-Tooth (CMT) disease is a peripheral nervous system disorder.
  • Demyelinating CMT (CMT1) has a high diagnostic yield, often linked to PMP22 gene duplication, but other genetic causes exist.

Purpose of the Study:

  • To investigate novel causal genes and mutations in a large cohort of individuals with CMT neuropathy using whole exome and whole genome sequencing.
  • To identify genetic variants contributing to the remaining cases of CMT1.

Main Methods:

  • Utilized whole exome and whole genome sequencing data from the GENESIS database for approximately 2670 individuals with CMT.
  • Employed Sanger sequencing to confirm mutation co-segregation with the CMT phenotype.
  • Analyzed patient-derived cells to assess protein expression and potential dominant-negative effects.

Main Results:

  • Identified a recurrent heterozygous missense variant, p.Thr1424Met, in the ITPR3 gene (encoding IP3R3) in 33 individuals across nine families.
  • Observed an unusual recurrence rate and confirmed autosomal dominant and de novo inheritance patterns.
  • All affected individuals presented with slow nerve conduction velocities, consistent with CMT1.
  • Documented significant variability in age of onset and clinical severity, even within families, for patients with the p.Thr1424Met mutation.
  • Provided evidence for a dominant-negative effect of the p.Thr1424Met mutation.

Conclusions:

  • The ITPR3 gene, specifically the p.Thr1424Met variant, is a novel cause of Charcot-Marie-Tooth type 1.
  • The p.Thr1424Met mutation exhibits a dominant-negative mechanism and leads to a clinically variable phenotype.
  • Further research into ITPR3 is warranted for understanding CMT pathogenesis and potential therapeutic targets.