New Insights into SPEG Protein and Muscle Disease
In a study published in the Journal of Cachexia, Sarcopenia and Muscle (JCSM), researchers at the University of Miami Miller School of Medicine, Boston Children’s Hospital, Brigham & Women’s Hospital and Harvard Medical School have shown how mutations in the SPEG protein can derail muscle function and cause disease.
Using a complex, multi-omic approach, the team showed how SPEG interacts with multiple skeletal and heart muscle proteins and regulates them.
“We have been studying SPEG for more than 10 years,” said Pankaj Agrawal, M.D., chief of the Division of Neonatology at the University of Miami Miller School of Medicine. “This is a critical protein for muscles and we are trying to understand how it works and find therapies.”
Developing the First Treatments for SPEG Conditions
There are no treatments for SPEG-related conditions. Motivated by the stories they hear about patients with congenital SPEG conditions, Dr. Agrawal’s team has been conducting in-depth, fundamental bench work to develop them.
In the United Kingdom, one family’s 2-year-old son was born with SPEG mutations that cause profound muscle weakness.
“He doesn’t have any muscle control,” said the boy’s father. “His neck and body are just floppy. He can lift his arms up a little and move side to side, but he can’t sit or talk. He understands what we’re saying and he tries to speak, but he can only make sounds we don’t understand.”
Dr. Agrawal and colleagues discovered the link between SPEG mutations and weak skeletal and heart muscles in 2014 and have been investigating the gene ever since. This latest paper produced a more holistic understanding of how SPEG mutations directly and indirectly influence muscle function.
Multi-Omic Research
In the study, the team combined several sophisticated research techniques, including transcriptomics (measuring RNA levels), proteomics (measuring protein levels) and interactomics (identifying SPEG-interacting proteins). SPEG is a kinase protein. It delivers phosphate molecules to other proteins to alter their function, a process called phosphorylation. To understand these relationships, the researchers also utilized phosphoproteomics.
“We found SPEG is phosphorylating some of the proteins associated with muscle contraction and are critical to that function,” said Dr. Agrawal. “It was a multi-omic approach to really understand this mechanism at the molecular level.”
These investigations showed that SPEG interacts with many proteins, including CMYA5, FSD2 and RyR1, which help form myospryn complexes that collectively make muscles contract.
Having dissected the SPEG pathway, Dr. Agrawal’s team will continue to investigate these proteins to better understand how they influence disease. The team is currently building a database of patients with SPEG mutations and have already been looking at cell and gene therapies that could modulate disease.
“We are going to look very hard at these proteins that interact with SPEG,” said Dr. Agrawal. “Previously, we identified a protein, called DNM2, which, when reduced in a disease model, can improve skeletal muscle function but not heart muscle. We see the patients and families who are suffering from these conditions, and it’s imperative that we do the difficult bench work to finally develop treatments.”
Tags: Division of Neonatology, Dr. Pankaj Agrawal, neonatology