Researchers Discover Novel Mutation in EGR2 Gene That Causes Severe CMT Type 3

A newly discovered mutation in the gene EGR2 causes a severe form of Charcot-Marie-Tooth disease type 3 (CMT3), according to a case report of a 56-year-old patient.

The report, titled “A de novo EGR2 variant, c.1232A > G p.Asp411Gly, causes severe early-onset Charcot-Marie-Tooth Neuropathy Type 3 (Dejerine-Sottas Neuropathy),” was published in Scientific Reports.

Mutations in more than 90 genes have been documented as causing CMT, and influence the way the disease presents itself from patient to patient. Among the known CMT-causing genes is EGR2 (early growth response 2), which codes for a protein of the same name.

EGR2 is a transcription factor — a protein that helps regulate how genes are expressed in a cell, that is, which genes are “turned on or off.” Specifically, EGR2 helps control the expression of genes needed for neurons to function properly.

Mutations that impair the ability of the EGR2 protein to perform this function have previously been linked to CMT3, also known as Dejerine-Sottas disease in its more severe forms, and to CMT4E.

“The severity and onset of peripheral neuropathy [nerve disease] caused by EGR2 variants is highly heterogenous [varied], and it is yet to be determined why this broad phenotypic [symptomatic] variability exists,” the researchers wrote.

In the case report, they describe a male patient who was 56 at the time of publication.

His symptoms, including abnormal fatigue and difficulty walking, were first noted when he was two. A nerve biopsy at the age of six confirmed a diagnosis of severe CMT3.

The patient experienced ongoing complications throughout childhood and into young adulthood, including the development of scoliosis, recurring migraines, and difficulty walking. At age 15, the patient required ankle surgery to stabilize the joint.

Examinations performed when he was in his 30s showed physical abnormalities, including muscle wasting in the extremities, lack of normal reflexes, and tremors. Additionally, nerve conduction studies (which measure how effectively nerves in the body can transmit electric signals) revealed significant functional deficits, and imaging of the brain revealed multiple lesions indicative of damage, including severe demyelinating (loss of the protective myelin layer around nerves) motor and sensory neuropathy.

By age 56, the patient’s motor functioning was severely impaired, and he was “unable to write, or use a knife and fork.”

Genetic sequencing studies were performed to identify the underlying cause of his severe form of CMT. Initial studies identified several genetic variations that were possible candidates; however, further analysis revealed that some of these were present in the patient’s relatives who did not have any of his symptoms, making it unlikely that those variants were the cause.

The analysis did suggest one variant as the cause: a mutation in EGR2 called either c.1232A>G or p.Asp411Gly, referring to the specific substitution at the DNA and protein levels, respectively.

Further analyses — including computer modeling and a comparison of EGR2 sequences across various species — indicated that this mutation changed a particular part of the EGR2 protein that is likely important to the protein’s ability to function properly. As such, it would be expected that the mutation, by altering this crucial part, would stop the protein from working as well.

To test this idea, the researchers constructed a model using cells in lab dishes. In simple terms, the cells were engineered with a gene encoding a fluorescent protein that could be turned “on” by the EGR2 protein. The cells were then given either mutated or wild type (normal) versions of EGR2, and the researchers measured how much of the fluorescent protein was produced — indirectly measuring how well each type of EGR2 protein turned the gene “on.”

Cells with the mutated protein produced significantly less of the fluorescent protein, supporting the idea that the mutation impairs the protein’s ability to function.

“[W]e have determined that a de novo missense EGR2 variant, c.1232A > G p.Asp411Gly, causes a severe and early onset [CMT3] phenotype by reducing the capacity for EGR2 to function as a transcription factor,” the researchers wrote.

“The phenotype [observable profile] is complicated by clinical features of white matter lesions and FMH [familial hemiplegic migraine] which may be a chance association, although it would be important to consider the possibility of central nervous system involvement in future cases of EGR2-related neuropathies [nerve diseases],” they said.