Novel GJB1 Gene Mutation Found as Cause of CMTX1 in 2 Brothers

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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An illustration of a strand of DNA highlights its double helix structure.

A never-before-reported mutation in the GJB1 gene was identified in a recent case report as the cause of X-linked Charcot-Marie-Tooth (CMTX1) disease in two brothers — one of whom had more severe symptoms than the other.

Both brothers showed elevated levels of a small RNA molecule called miR-206 — known to be important for muscle development.

The researchers speculated that alterations in miR-206 levels, as well as lifestyle differences between the siblings, may have contributed to the varying effects of CMTX1 on the brothers.

The report, “Distinct Phenotypic and microRNA Expression in X-Linked Charcot–Marie–Tooth Correlated with a Novel Mutation in the GJB1 Gene,” was published in the journal Muscles.

A quartet of scientists from the University of Padova, in Italy, described the case of the two brothers, who both showed symptoms indicative of CMT. The brothers also have a cousin with similar symptoms, who was not included in the report.

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The older brother, now age 55, had begun experiencing muscle wasting in his late 20s. He was able to walk, though his gait was uncoordinated. He also had difficulty grasping objects with his hands and performing fine motor skills like manipulating a zipper or writing.

The younger brother, age 47, also displayed muscle wasting with muscle weakness and a tremor. However, his hand dexterity was not impaired, and muscle wasting overall was less extensive than in his brother.

Notably, the siblings had very different lifestyles. While the elder brother was a heavy smoker who was not very physically active, the younger brother maintained a more active lifestyle due in part to a career in the military.

That led researchers to believe that part of the reason for the differences in how the two were affected by CMTX1 might be partially attributable to lifestyle.

“The two affected patients had different personal adaptations to the neuropathy disability. While the older sibling, an inactive, smoking, depressed man, had gait difficulty and presented a chronic invalidating neuropathy [nerve damage], both in the upper and lower extremities, the younger brother was a military pilot and had minimal weakness, a slight tremor mostly in the right hand, and preserved fine motor function,” the scientists wrote.

Both brothers underwent genetic testing, and the results identified a mutation in the gene GJB1 that had never before been reported. Mutations in this gene, which provides instructions for a protein that is important for maintaining connections between neighboring cells, are known to cause X-linked Charcot-Marie-Tooth; overall, more than 40 genes are known to be involved with CMT.

The specific mutation, identified in both brothers, was a deletion of seven nucleotides or “letters” of the genetic code, occurring in exon 2. Exons are the bits of genetic information needed to make proteins.

Analyses of the sequence indicated that the mutant gene would lead to the production of a truncated protein that would likely not be able to fulfill its typical functions.

The brothers’ blood also showed elevated levels of miR-206, a small RNA molecule that is known to be important for the growth and development of muscles. The levels of miR-206 were increased by about four times in the elder brother, and about 10 times in the younger.

“We suggest that the level of miR-206 might reflect the different muscle mass observed, with less [muscle] atrophy in the younger brother,” the scientists concluded, adding that their report would serve to “further expand the phenotypic [disease characteristics] spectrum associated with the disease.”