New MCM3AP Gene Mutation Linked to CMT in Chinese Girl

A newly identified mutation in the MCM3AP gene caused Charcot-Marie-Tooth disease (CMT) in a girl with early motor development delay, a study reports.

Findings also suggest that mutations in this gene that result in no functional MCM3 protein are associated with more severe symptoms, including a delayed ability to walk.

The study, “Genetic spectrum of MCM3AP and its relationship with phenotype of Charcot‐Marie‐Tooth disease,” was published in the Journal of the Peripheral Nervous System.

To date, mutations in more than 90 different genes have been reported to cause CMT. Mutations in MCM3AP were first reported as a cause of CMT in 2017, with more recent studies expanding the number of known MCM3AP mutations associated with the disorder.

Researchers in China detailed the case of a girl with CMT who was the only child of healthy Chinese parents. She experienced early delays in reaching motor milestones, with independent walking beginning at 17 months of age. At 5 years old, the patient started to experience numbness and muscle weakness that slowly progressed.

Six years later, she developed foot problems — pes cavus, or high arch, and foot drop — and moderate muscle atrophy (shrinkage) of the limbs. Nerve conduction studies demonstrated abnormally low activity in the nerves that help control movement in the arms and legs. Tendon reflexes, which refer to nerve reflexes that determine muscle contraction upon tapping, were absent.

Genetic analysis revealed the patient had mutations in both copies of the MCM3AP gene (one copy from each biological parent).

The paternal copy had a mutation known as c.2633G>A, which was previously associated with CMT. It is specifically a missense mutation, a type of mutation that changes one amino acid in the protein product. In this case, arginine was replaced by histidine. The maternal copy had a novel mutation, referred to as c.5634-1G>T.

Protein-coding genes such as MCM3AP provide instructions for making a protein, but these instructions are not all kept together. Instead, the gene has exons — regions that code for a protein — that are separated by introns, which do not code for proteins. When the gene is converted into RNA, that RNA undergoes splicing to remove the introns before the protein product is made.

Subsequent analysis found that the c.5634-1G>T mutation causes a splicing defect that results in a shorter RNA molecule and in lower levels of RNA in the blood.

An ongoing challenge in CMT research is finding connections between particular genetic mutations (genotype) and the resulting symptoms (phenotype). As such, the scientists analyzed the genotype-phenotype relationships in CMT caused by MCM3AP mutations, using data from their study in combination with previously published reports.

They divided patients into two groups: One group consisted of nine people with at least one null mutation in MCM3AP, which makes the gene entirely non-functional. The other group included eight individuals with missense mutations in both gene copies.

In general, patients with missense mutations tended to have less severe disease than those in the null group. Patients with null mutations tended to be younger at disease onset (2.4 vs. 7 years old), and had higher rates of independent walking delay (100% vs. 37.5%) and intellectual disability (77.8% vs. 37.5%) than patients with missense changes. However, only the difference in independent walking delay was statistically significant, which could be due to the small number of patients studied.

Overall, the study adds to the growing body of work that demonstrates MCM3AP as a disease-associated gene in CMT, and provides some clues to the relationship between specific mutation types and disease severity.

“Our findings expand the genetic spectrum of MCM3AP and suggest that genotype-phenotype correlation would help genetic counseling of MCM3AP in CMT patients,” the researchers wrote.