Scientists Uncover New Insights Into Causes of Limb-Girdle Muscular Dystrophy

Scientists say they know which isoform of a key protein is most likely to lead to a rare type of muscular dystrophy.

Investigators have uncovered a mechanism that appears to trigger a rare form of muscular dystrophy.

Limb-girdle muscular dystrophies (LGMD) is a category of rare hereditary disorders, in which patients experience wasting and weakness in the hips and shoulders. The disease can vary significantly in severity and progression based on the specific genetic mutations behind an individual case.

Scientists at the Autonomous University of Barcelona (UAB) wanted to find out more about one particular type of the disease, LGMD type 1G (LGMD1G). To do so, they examined a little-understood protein called hnRNPDL. They found that one of the protein’s isoforms appears to accelerate the formation of amyloid fibrils, a trait that is tied to certain genetic mutations that inhibit the performance of the protein.

The findings were published January 28 in Cell Reports. Salvador Ventura, PhD, chair of the department biochemistry and molecular biology at UAB, said the study marks the first time investigators have been able to concretely tie genetic mutations to hnRNPDL protein aggregation.

“For some ribonucleoproteins, for example hnRNPD, there is a lot of information about their function and they have been extensively characterized,” Ventura told The American Journal of Managed Care®. “However, this is not the case for hnRNPDL.”

The protein was first identified back in 1998, but it would be 16 years before the was genetic mutation behind LGMD1G would be identified for the first time. Ventura has a couple of possible hypotheses for the lack of study of hnRNPDL.

“The reason that could explain why there are not so much studies about this protein might be because it is highly insoluble and difficult to work with it,” he said. “Moreover, LGMD is a very minor disease that it could have not drawn so much attention for the research groups.”

In his study, Ventura and colleagues used in vitro and in human cells, as well as a transgenic model of the Drosophila fruit fly, to examine the three isoforms in which the protein is found.

Those isoforms have 1, 2, or 3 protein domains.

The investigators found that the isoform with 2 domains had the greatest tendency to form aggregates, something that surprised the researchers, in part because it is the most common isoform.

Conversely, the isoform with 3 domains was more prone to undergo phase separation, a process that seems to correlate with lower levels of aggregations.

Ventura cautioned that the research is just a first step. While scientists know which mutation of hnRNPDL is linked with LGMD1G, they still don’t know the specific consquences of the mutation, something that would be necessary before a therapy could be developed.

“However, thanks to our study, we expand the knowledge about hnRNPDL isoforms and the effect of mutations,” he said. “We get important information about the predominant isoform, which is the isoform with higher aggregation potential and in which mutations accelerate this process.”

Ventura said his team’s hypothesis is that LGMD1G might lead to a loss of function of hnRNPDL, leading to misregulation of gene expression.

“Further studies to find the genes affected by loss of hnRNPDL responsible for LGMD1G should be performed,” he said. “Possible therapies avoiding hnRNPDL aggregation could help to treat the disease.”


Batlle C, Yang P, Coughlin M, et al. hnRNPDL phase separation is regulated by alternative splicing and disease-causing mutations accelerate its aggregation. Cell Reports. 2020;30(4). doi:10.1016/j.celrep.2019.12.080

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