Mutation in IGFBP7 gene linked to rare phenomenon of ALS reversal
Researchers study IGFBP7 protein tied to partial or full recovery in patients
A mutation in the IGFBP7 gene is associated with a very rare phenomenon in which people with amyotrophic lateral sclerosis (ALS) have a reversal in disease progression and experience partial or full recovery, a new study reports.
Because the mutation results in less production of the resulting protein IGFBP7, the findings suggest that inhibiting that protein may have therapeutic benefits for ALS patients. However, further studies will be needed to fully understand the gene’s role in people with traditional ALS progression.
“This work provides a starting point to explore how biological reversals of ALS occur and how we might be able to harness that effect therapeutically,” Richard Bedlack, MD, PhD, co-author of the study and a professor at Duke University School of Medicine in Durham, North Carolina, said in a Duke Health news story.
According to the researchers, their report marks the first analysis of the genome, or a person’s complete set of DNA, among patients who have experienced ALS reversal.
The study, “Genetic Associations With an Amyotrophic Lateral Sclerosis Reversal Phenotype,” was published in the journal Neurology.
Scientists look for genetic link in cases of ALS reversal
ALS typically is a progressive disease, meaning that symptoms get worse as time goes on. There are exceptions, however. In a minority of cases, patients initially show signs indicative of ALS and meet the criteria for an ALS diagnosis, but then their symptoms slowly ease and remain mild or disappear entirely in the long term. These cases of so-called ALS reversal have been documented for decades, but no clear cause has ever been identified.
Further, this team of scientists noted that, while they’ve identified more than 50 cases with “a unique ALS reversal phenotype,” or a set of observable traits, “we have found that this phenotype does not have identifiable common environmental factors.”
Now, these scientists from Duke conducted a genome-wide association study, or GWAS, looking to determine whether genetics could be playing a role in this rare, unexplained phenomenon. GWAS is a fairly straightforward type of analysis that simply involves comparing genetic mutations in two groups (e.g., ALS reversal or not) and looking for mutations that are significantly more common in one group than the other.
For this GWAS, the researchers used genetic data from 22 people who had experienced ALS reversal, who were followed in a patient registry (NCT03464903) launched at Duke in 2018.
“While ALS reversals have been described in the literature since the 1960s, to our knowledge, this is the first report of a genomic analysis in this ultra-rare population,” the scientists wrote.
The data was compared with genetic information from two control groups: one involving 103 ALS patients followed in a natural history study (NCT02327845) from the CReATe Consortium, and another comprising 140 patients from the Target ALS cohort.
IGFBP7 gene mutation tied to 12 times greater likelihood of ALS reversal
The results zeroed in on a particular mutation in the IGFBP7 gene, referred to as rs4242007 C. This mutation was associated with an up to 12 times greater likelihood of ALS reversal.
The researchers noted three of the reversal patients had this mutation in both copies of the gene — one is inherited from the mother and one from the father. None of the patients with typically progressing ALS had this mutation in both copies, however.
“We found an IGFBP7 [mutation] that is significantly associated with the phenotype of ALS reversal,” the researchers wrote.
The IGFBP7 gene provides instructions to make a signaling protein called IGFBP7, which is part of the IGF-1 molecular signaling pathway. In particular, IGFBP7 works as an inhibitor of the IGF-1 receptor, preventing it from exerting its effects in cells such as boosting survival.
“This suggests that the IGF-1 pathway should be further studied as a potential target for future ALS treatments,” said Jesse Crayle, MD, co-author of the study, who’s now at Washington University in St. Louis.
We found an IGFBP7 [mutation] that is significantly associated with the phenotype of ALS reversal.
Interestingly, the identified mutation is not in the part of the IGFBP7 gene that actually contains instructions for making protein, but analyses suggested that this mutation causes the gene to be less active, leading to reduced production of the protein. That causes the IGF-1 receptor to be more active, which may contribute to the reversal of ALS symptoms.
The researchers noted other studies have indicated that IGFBP7 protein levels are increased in models of ALS as well as Alzheimer’s, another neurological disease. Taking these data collectively, the scientists speculated that reduced levels of this signaling protein might act to slow or even reverse ALS progression, though they stressed that additional research will be needed to test this hypothesis.
Most of the people included in this analysis were of European descent, the team also noted, so additional studies are needed to test if this mutation also is associated with ALS reversal in other racial and ethnic groups.
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