This gene has not previously been implicated in CMT, the researchers said.
The study, “Isoform-specific loss of dystonin causes hereditary motor and sensory neuropathy,” was published in Neurology Genetics.
CMT is caused by genetic mutations that affect the function of peripheral nerves — those that control motor and sensory functions. So far, more than 80 genes have been identified as causes of various types of CMT.
Understanding these mutations may help develop better strategies for treatment and care. Therefore, identifying and characterizing CMT-causing mutations remains an ongoing area of research.
The new study reported data from two biological siblings with CMT. The older sibling first experienced difficulty walking at age 13, and was diagnosed with CMT at 29, when she was first seen at the researchers’ clinic. She experienced walking difficulty and muscle weakness throughout the subsequent decades; by age 55, she was using a walker.
The patient’s younger brother was diagnosed with CMT at age 18, and was first seen at the researchers’ clinic when he was 46.
Both siblings had symptoms consistent with CMT type 2, also called axonal CMT because nerve fibers, or axons, are impacted in this disease type. An older sibling and their father did not show signs of CMT.
The researchers performed whole-exome sequencing (WES) on all three siblings, both the two with CMT and the one without. WES is a technique in which only the parts of the genome that code for proteins — less than 2% of the total genome — is sequenced.
The two siblings with CMT both had mutations in the gene DST — a gene that had not been previously identified for involvement with CMT.
Specifically, the siblings had compound heterozygous mutations, which means that both copies (one from each biological parent) were mutated, but not in the same way. The mutations were termed c.250C>T and c.8283+1G>A, in reference to the exact change that occurs in the genetic code.
The unaffected sibling had one mutant copy of DST (specifically c.250C>T) and one non-mutated copy. Presumably, the non-mutated copy was able to functionally compensate for the mutated one, which explains why this brother did not develop CMT.
“We have collaborated with this family for 30 years, and now we finally have an answer, and the answer was a new genetic cause of neuropathy,” Steven S. Scherer, MD, PhD, a professor at the University of Pennsylvania and study co-author, said in a press release.
DST encodes a protein called bullous pemphigoid antigen 1 (BPAG1). Depending on exactly how this protein is produced and processed, there are multiple types (BPAG1-a, BPAG1-b, etc.) and subtypes (BPAG1-a1, BPAG1-a2, etc.) of the protein, which are called isoforms.
Detailed analysis of the identified mutations suggested that the c.250C>T mutation would specifically impair the production of the isoforms BPAG1-a2 and BPAG1-b2. The mutation c.8283+1G>A was predicted to affect all BPAG1-a and BPAG1-b isoforms.
“Thus, the loss of a2 and b2 isoforms is correlated with axonal neuropathy,” the researchers concluded.
They noted that the connection between these isoforms and axon problems also has been identified in mouse studies. Specifically, experiments in mice have implicated the isoform BPAG1-a2 in the development of neuropathy.
“Thus, the loss of BPAG1-a2 specifically could be the cause of the neuropathy seen in dt/dt mice and our patients; whether the loss of b2 contributes to the phenotype remains to be determined,” the researchers wrote.
Overall, this study identified a new genetic cause of CMT, which may be important for developing future treatment strategies.
“We are in the era where treatments for genetic diseases are possible,” Scherer said. “This brother and sister stand to benefit from that approach because we know the gene that is missing, and if we could replace it, that should at least prevent their progression.”
Scherer said researchers continue to work to identify what he says are likely many more mutations that can cause CMT.
“We are determined to fill in the blanks of this giant jigsaw puzzle,” he said.
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