Disease in Family Traced to 2 Separate Mutations Working ‘in Tandem’

Disease in Family Traced to 2 Separate Mutations Working ‘in Tandem’
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A mutation in the EGR2 gene that by itself does not cause disease was seen to result in Charcot–Marie–Tooth disease in a Spanish family, due to the concurrent presence of another non-disease causing variation in the LITAF gene, a case study reported.

The deficiency in both genes — which appear to act “in tandem” — affected the production of myelin, the fatty substance that wraps around nerve fibers to ensure proper neuron communication.

The study, “Novel EGR2 variant that associates with Charcot-Marie-Tooth disease when combined with lipopolysaccharide-induced TNF-α factor T49M polymorphism,” was published in the journal Neurology Genetics.

Charcot-Marie-Tooth disease, or CMT, is caused by mutations found in over 30 distinct genes, and researchers estimate that at least 30 more CMT-causing genes are yet to be discovered.

EGR2, the gene that encodes for the early growth response 2 (ERG2) protein, controls the production of myelin by Schwann cells. Mutations in this gene are known to cause as CMT type 1D.

Researchers in Spain reported finding a new mutation in EGR2, called P397H, in a 54-year-old woman with Charcot-Marie-Tooth. The woman was diagnosed at age 47 with chronic damage to nerve fibers. But she began showing symptoms of muscular shrinkage (atrophy) and walking instability in early childhood.

Neurological exams revealed moderate to severe atrophy in her upper and lower limbs together with weakness, arched feet, and shortening of the Achilles tendon.

The patient had moderate disease severity, and low or absent reflexes. Motor nerves, those controlling movement, were also conducting electrical signals at a much slower speed than normal, particularly in the lower limbs.

Genetic analysis of 34 CMT-related genes showed no disease-causing mutations in any of them, but the woman had a novel mutation (P397H) in the EGR2 gene and a previously described variant (a variation in the DNA sequence) in the LITAF gene.

Mutations in LITAF have been reported to cause CMT type 1C, but this particular variant was not known to cause disease.

This led researchers to explore the association of the new EGR2 mutation with CMT.

They found that others in the patient’s family carrying only the LITAF gene variant or only the EGR2 mutation had no disease symptoms. Only those carrying both mutations developed symptoms of CMT.

The team then inserted the EGR2 mutation into lab-grown cells to understand how it affected the protein’s function. The mutated and normal protein were similar in many ways, including in protein levels, protein stability, nuclear localization, and DNA binding. But the mutation caused its protein to have much less activity than the normal protein.

In people carrying only the EGR2 mutation, the remaining activity is enough to maintain myelin production. But the variant in the LITAF gene — which caused the LITAF protein to be less stable and less abundant — indirectly affected EGR2 protein function. It caused EGR2 activity to drop below acceptable levels, diminishing the ability of Schwann cells to produce myelin.

“Our data support that the LITAF loss-of-function interferes with the expression of the transcriptional-deficient EGR2 P397H mutant hampering Schwann cell differentiation and suggest that in vivo both genes act in tandem to allow the proper development of myelin,” the researchers wrote.

Patricia holds her Ph.D. in Cell Biology from University Nova de Lisboa, and has served as an author on several research projects and fellowships, as well as major grant applications for European Agencies. She also served as a PhD student research assistant in the Laboratory of Doctor David A. Fidock, Department of Microbiology & Immunology, Columbia University, New York.
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Inês holds a PhD in Biomedical Sciences from the University of Lisbon, Portugal, where she specialized in blood vessel biology, blood stem cells, and cancer. Before that, she studied Cell and Molecular Biology at Universidade Nova de Lisboa and worked as a research fellow at Faculdade de Ciências e Tecnologias and Instituto Gulbenkian de Ciência.
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Patricia holds her Ph.D. in Cell Biology from University Nova de Lisboa, and has served as an author on several research projects and fellowships, as well as major grant applications for European Agencies. She also served as a PhD student research assistant in the Laboratory of Doctor David A. Fidock, Department of Microbiology & Immunology, Columbia University, New York.
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