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

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.