French scientists have linked another mutation of the GDAP1 gene to Charcot-Marie-Tooth disease.
But in this case, the mutation was in an area of the gene that does not code for the production of protein.
The discovery stemmed from a genetic analysis of a family from Sri Lanka with six children, two of whom had CMT.
Researchers titled their report, published in the journal Neurogenetics, “WES homozygosity mapping in a recessive form of Charcot-Marie-Tooth neuropathy reveals intronic GDAP1 variant leading to a premature stop codon.”
The sisters who developed CMT started walking when they were about 2 years old. They began experiencing muscle weakness in their legs when they were about 3. The symptoms had worsened significantly by the time they were 15.
At this point, the girls had lost movement in their arms and legs. They also had contractures — or shortened tendons, muscles or connective tissue — that prevented them from extending their hands. And they were experiencing muscle palsy, or paralysis.
Severe walking impairment led to them being wheelchair-bound by the age of 16.
“Sensory complaints were minor, and were characterized by a diminished vibratory sense in all four limbs,” the researchers reported. “There was no cognitive or cerebellar [brain] impairment and there were no ophthalmologic [vision] symptoms.”
In addition to their movement problems, the sisters experienced lung function impairment. The lung capacity of one of them was only 57 percent, and the other 71 percent.
None of the other family members had movement problems.
To try to identify the gene responsible for the sisters’ symptoms, the researchers did a genetic analysis using a method called whole-exome sequencing.
They could not detect any gene mutations known to be linked to CMT. But they did identify 53 variations in DNA sequences that do not code for the production of protein. Eleven of the variations were clustered close to the GDAP1 gene.
Further evaluation showed that one of the variations could trigger a modification of the gene that generated an abnormally short version of GDAP1 protein.
The researchers discovered that the sisters had two copies of the variation, while their healthy brothers had only one copy. This indicated that the girls had inherited the variation in a recessive pattern — that is, one in which two copies are needed to cause a disease.
“To our knowledge, no deleterious mutation has been demonstrated in GDAP1 outside of coding sequences,” the researchers reported.
Scientists have linked several genes to CMT. But identifying the specific mutation that leads to the disease’s harmful effects on a patient can be challenging. Whole-exome sequencing can help, but selecting the right genes to review is a critical step.
In this case, the most suitable candidate was the GDAP1 gene. The girls’ symptoms were in line with those seen in other cases of CMT linked to GDAP1, further supporting the diagnosis.
“This work is the first to describe a deleterious mutation” in a non-coding area of the GDAP1 gene, the team wrote, adding that the finding “emphasizes the importance of [properly] interpreting molecular analysis.”