ITPR3 Mutations Can Cause Intermediate Form of CMT, Study Says

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by Diana Campelo Delgado |

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CMT2A natural history

Mutations in the ITPR3 gene appear to cause an intermediate form of Charcot-Marie-Tooth disease (CMT) that shows axonal degeneration and demyelination, a recent study suggests.

While IP3R3 — the protein coded by ITPR3 — is thought to be needed to maintain the protective myelin sheath, defects in this protein were also seen to impair calcium signaling, which may contribute to neuronal damage.

The study, “Dominant mutations in ITPR3 cause Charcot-Marie-Toothdisease,” was published in the journal Annals of Clinical and Translational Neurology.

Genetic alterations in the ITPR3 gene have been proposed as a potential cause of CMT, leading to disease in an autosomal dominant manner — meaning that only one copy of the gene needs to be mutated for a person to exhibit disease symptoms. Normally, a person inherits two copies of a gene, one from each parent.

However, the mutations described to date have not been subject to functional studies to confirm their disease-causing properties. They have also not been identified and studied in additional families with CMT.

In this new study, a team of researchers at the University of Helsinki, in Finland, examined the genome of four individuals with CMT from the same family, showing an autosomal dominant pattern of inheritance, and a single individual from another family.

Individuals in the family with the disease showed a late onset, at around age 30, of damaged nerve cells (neuropathy) with loss of myelin, the protective layer that surrounds nerve cells, and axonal degeneration. The symptoms progressed gradually over time in these patients, with one patient showing severe muscle weakness and atrophy around age 64.

The genome sequencing identified a mutation, called p.Val615Met, in the ITPR3 gene that was present in the members of the family who had the disease, but not in the individual of the family unaffected by the disease.

This individual had early disease onset at age 4 with loss of myelin and damaged nerve cells. His condition was progressive, leading to severe muscle atrophy below the knees and atrophy of leg and hand muscles by age 16. The researchers found that he had a de novo mutation, called p.Arg2524Cys, in ITPR3.

Using computational tools, the researchers predicted that the two identified ITPR3 variants are damaging to protein structure and/or function. Interestingly, the amino acids, the building blocks of proteins, that were changed as a result of these mutations are highly conserved among species, demonstrating their key role in protein function.

Due to the different locations of the mutations within the IP3R3 protein, researchers hypothesize that these mutations might have different effects on IP3R3 function, while also influencing disease severity.

Furthermore, the team also functionally analyzed skin cells (fibroblasts) from two individuals of the affected family, using different techniques.

Altered calcium signaling in patient cells carrying the p.Val615Met mutation suggest that the variant has a dominant-negative effect on IP3R3 function. The effect appears to be subtle, which is consistent with late onset and slow disease progression.

However, the researchers recognize the limitations of these findings, since the results may be influenced by other genetic differences between control and patient cells, in addition to the ITPR3 mutation. Also, skin cells might not accurately reflect the effects of the mutation in nerve cells or myelin-producing cells.

“Our results provide further evidence that ITPR3 is a disease gene for CMT. Additional studies, ideal in neuronal or animal models, will be needed to elucidate the effects of the disease variants on IP3R3 function and evaluate the potential of targeting Ca2+ [calcium] flux as a therapeutic target in CMT,” the team concluded.