Facioscapulohumeral muscular dystrophy (FSHD) is an inherited disorder characterized by progressive muscle degeneration, initially involving in the face, shoulder, and upper arms and progressing to affect all skeletal muscle groups. While there are no treatments that can reverse the effects of FSHD, several drug companies are working on new therapies. FSHD is caused by inappropriate expression of the transcription factor DUX4 in skeletal muscle. During normal embryonic development, DUX4 is expressed for a very short and specific time and targets multiple genes for transcription, but in adulthood, DUX4 and its targets are silenced. In individuals with FSHD, muscle biopsies reveal that DUX4 is aberrantly expressed and its genetic targets are reactivated, and their abundance correlates with disease progression.
Treatments for FSHD could come in the form of silencing DUX4 expression. Dr. Stephen Tapscott and his lab have previously shown that DUX4 RNA expression and the downstream DUX4 targets can be silenced using an antisense siRNA and several drug companies are developing therapies to suppress DUX4 expression. To determine whether these drugs suppress DUX4 in clinical trials, it would be useful to have a way to monitor DUX4 activity throughout the entire body. Muscle biopsies can be useful, but these procedures are invasive and only give insights about disease progression in a single tissue. Identifying a marker for FSHD and DUX4 activity that circulates in the blood would solve both of these issues: Doctors would have information on how FSHD is progressing through the whole body, and patients would only need to have their blood drawn. In a recent study published in Human Molecular Genetics, researchers in the Tapscott lab, in collaboration with scientists at Avidity Biosciences, identify the protein KHDC1L as a circulating biomarker for DUX4 activity during FSHD.
Myoblasts are precursor cells for differentiated muscles that can be grown in culture. The team began their work by using DUX4-expressing myoblasts to identify DUX4 gene targets that become secreted proteins. Using mass spectrometry, they found several secreted proteins from DUX4-expressing cells including KHDC1L. This protein was particularly interesting to researchers because its gene promoter has a DUX4 binding site, KHDC1L mRNA is present in FSHD but absent in healthy muscle biopsies, and it is not expressed by other adult tissues.
The biological function of KHDC1L is unknown, and few tools existed to study the gene. The group next developed monoclonal antibodies to detect KHDC1L protein. Using these new antibodies, they were again able to confirm that KHDC1L protein is released from DUX4-expressing myoblasts. Further work confirmed that one of their antibody clones was highly specific for KHDC1L, giving researchers a new tool to study this protein.
At this point they initiated a collaboration with scientists at Avidity Biosciences to develop assays for detecting KHDC1L in FSHD plasma. This proved especially challenging because reagents to detect KHDC1L did not exist prior to this work. They attempted mass spectrometry-based approaches, but due to reproducibility issues, the team moved on to other techniques.
Next, they tried using an electrochemiluminescence immunoassay to detect protein from plasma samples. They used the highly specific antibody to capture KHDC1L from patient plasma and another antibody clone to detect how much KHDC1L protein bound to the capture antibody. KHDC1L abundance in FSHD plasma trended higher than that in healthy volunteers, but ultimately the group felt that they needed a more sensitive assay to detect KHDC1L.
Finally, the team tried the SomaScan 7K aptamer proteomics platform. This technique uses high affinity and high specificity DNA aptamers to bind KHDC1L protein in plasma samples. This sensitive approach revealed that circulating KHDC1L levels from FSHD subjects were significantly higher than those from healthy volunteers.
This work identified a new circulating biomarker for FSHD, developed new reagents to study it, and validated approaches to quantify the biomarker in FSHD plasma. Recently, Avidity Biosciences has developed an antisense RNA drug to silence DUX4 expression in the muscle cells of FSHD subjects. This trial is currently underway, and circulating KHDC1L levels are being measured as a candidate biomarker that might show whether there is a biological response to the therapy. Tapscott is excited by this ongoing work. “Although efficacy will need to be determined in a larger Phase III study currently underway, it is gratifying that our earlier work on disease mechanism and the more recent identification of a candidate circulating biomarker described in this current publication might have provided a framework for clinical intervention in FSHD,” he says.
For Tapscott, this work is a prime example of how studying basic science and human biology can make meaningful improvements in patients’ lives. He began his career at Fred Hutch as a postdoctoral fellow in Dr. Hal Weintraub’s lab, whose lab was one of the first groups to use antisense RNA to suppress gene expression in eukaryotes. “At that time, I thought antisense would rapidly be exploited for therapies,” he reflects, “Now many years later the first treatment for FSHD might be based on the antisense technology discovered at the FHCC, which targets a gene validated as the cause of FSHD in part by work at the FHCC, and success might be measured by a biomarker developed at the FHCC.”
The studies in the Tapscott lab were led by Nick Sutliff, a research technician who is now in the MD/PhD Medical Scientist Training Program at UT Southwestern. This work was supported by funding from the National Institutes of Health and the Fred Hutch Proteomics Shared Resources. Dr. Stephen Tapscott has served as a consultant for Avidity Biosciences and currently has a Sponsored Research Agreement with Avidity.
Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium Member Dr. Stephen Tapscott contributed to this work.
Sutliff NA, Chao E, Bennett SR, Nip Y, Lakhdari O, Canton DA, Zhu Y, Tapscott SJ. 2026. Identification of KHDC1L, a DUX4-regulated protein, as a novel plasma biomarker in facioscapulohumeral muscular dystrophy. Hum Mol Genet. 2026 Feb 9;35(2):ddaf183. doi: 10.1093/hmg/ddaf183.
Kelsey Woodruff is a PhD candidate in the Termini Lab at Fred Hutch Cancer Center. She studies how acute myeloid leukemia cells remodel the sugars on their membranes to reprogram cancer cell signaling. Originally from Indiana, she holds a bachelor's degree in Biochemistry from Ball State University. Outside of lab, you can find her crocheting and enjoying the Seattle summers.
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