Study Reveals Key Sequences for Normal Expression of Critical Gene in CMT1A

José Lopes, PhD avatar

by José Lopes, PhD |

Share this article:

Share article via email
CMT genetic mutations


Specific genetic sequences are critical for normal expression of Pmp22, the critical gene in Charcot-Marie-Tooth disease type 1A (CMT1A), a new study shows.

The study, “Regulation of the neuropathy-associated Pmp22 gene by a distal super-enhancer,” was published in the journal Human Molecular Genetics.

CMT1A is caused by an extra copy of the peripheral myelin protein 22 (PMP22) gene, which codes for the PMP22 protein, a key component of the protective layer of nerve fibers called myelin. This genetic alteration leads to excess levels of protein, which reduces the amount of functional PMP22 and disrupts myelin.

Studies in animal models of CMT1A linked altered Pmp22 gene expression to damage in peripheral nerves, also known as peripheral neuropathy. These studies also showed that reduced levels of Pmp22 messenger RNA (mRNA), which contains the information for protein production, can ease neuropathy symptoms. As a result, modulation of Pmp22 expression became a potential target for drug development.

Patients with mild CMT-like symptoms revealed double copies of genetic sequences upstream of PMP22, but not the PMP22 gene itself. Molecular analyses found high levels of so-called “active enhancers” of gene expression, as well as binding sites for molecules (transcription factors) that regulate expression of PMP22 and other genes involved in the formation of myelin.

Subsequent studies in nerve injury models showed that, following peripheral nerve injury, many of these “active enhancers” disappeared, which was associated with reduced levels of Pmp22 mRNA.

The researchers conducted an in vitro molecular study to evaluate the impact of deleting this “super enhancer” cluster on Pmp22 expression.

Results revealed a significant reduction in the production of Pmp22 mRNA. The data further revealed that a promoter — a genetic sequence that activates gene expression — known as P1 and specific of Schwann cells is disproportionally more affected by the loss of the “super-enhancer.” Of note, Schwann cells form myelin in peripheral nerve fibers.

“These data show for the first time the requirement of these upstream enhancers for full Pmp22 expression,” the researchers wrote. The findings also provide an explanation for how double copies of these genetic sequences lead to CMT-like symptoms in humans, they added.

The authors observed that future development of an animal model with deletion of this “super enhancer” may further explain its role on Pmp22 expression at specific developmental stages.