Study Identifies CMT-Causing Mutations in Novel Gene

A new study reports two mutations in the gene C1orf194 that cause Charcot-Marie-Tooth disease (CMT), adding to the body of knowledge about genetic causes of the condition.

The study, “Mutations in C1orf194, encoding a calcium regulator, cause dominant Charcot-Marie-Tooth disease,” was published in the journal Brain.

More than 90 genes have been linked to the development of CMT, but the underlying cause still isn’t clear in as many as three-quarters of families affected by CMT.

In this new study, several members of affected Chinese families (including people with and without CMT) underwent genetic screening in the form of whole exome sequencing, which determines the sequence of the parts of the genome that actually code for a protein (around 1.5% of the total genome).

Two mutations in the gene C1orf194 were identified: c.365T4A (p.I122N) and c.83A4T (p.K28I). The first name refers to the DNA-level change; the name in parentheses indicates the resultant change in the sequence of the protein.

Within families, these mutations segregated with CMT — people with CMT also had the mutation, and people without didn’t. Additionally, the mutations were not detected in anyone in a broader cohort without CMT; the researchers also noted that these particular regions of C1orf194 are well-conserved in mammals from humans to cats, indicating that they are important for the normal function of the encoded protein — and, by extension, supporting the idea that these mutations could cause problems.

Among those studied, people with the p.K28I mutation tended to have CMT type 1; those with the p.I122N mutation tended to have an intermediate form of the disease. Both mutations caused CMT in an autosomal dominant pattern, meaning only one copy of the mutant gene was necessary to cause CMT.

To further understand these mutations, the researchers generated mice with the p.I122N mutation. These mice had lower body weights and exhibited behaviors typical of neuropathies (nerve diseases), including abnormal “clasping” movements of the hind limbs. Microscopic studies also revealed cell-level evidence of nerve abnormalities and damage.

Additionally, by looking at patterns of protein production in the nerve cells of these mice, the researchers noticed that many of the proteins nerve cells use to regulate calcium levels were irregular. Further analysis revealed dysregulated calcium signaling in these cells, which may be a mechanism for how C1orf194 mutations lead to disease — although future studies will be needed to more concretely understand such mechanisms.

The researchers specifically noted that they were “unable to conclude whether the genetic mechanisms of these two mutations are associated with a gain or loss of function,” meaning that it’s still not clear whether the mutations stop C1orf194 from working or make it do something extra that it shouldn’t do.

Still, this study shows that C1orf194 mutations can cause CMT, adding to the pantheon of known genes that can cause the disease. Better understanding these genes may aid in diagnosis or even the development of therapies.

“These findings describe a novel protein with vital functions in peripheral nervous systems and broaden the causes of Charcot-Marie-Tooth disease, which open new avenues for the diagnosis and treatment of related neuropathies,” the authors wrote.