A Comprehensive Review of MFM13
This blog provides a brief overview of a newly published review in BBA – Molecular Basis of Disease on myofibrillar myopathy type 13 (MFM13) caused by HSPB8 frameshift mutations. The paper brings together previously fragmented research, covering disease biology, clinical features, underlying mechanisms, and emerging therapeutic approaches - marking an important step toward improved understanding and future treatment.
A Comprehensive Review of MFM13: Molecular, Cellular, and Clinical Aspects of HSPB8 Frameshift Mutations
We are proud to share a major new publication that represents months of work, collaboration, and dedication to the MFM13 community.
A new review article titled "Molecular, cellular, and clinical aspects of myofibrillar myopathy caused by HSPB8 frameshift mutations" has been published in BBA - Molecular Basis of Disease (Elsevier). The paper was co-authored by Dr Wenli Zhou, Veronica Marchesi, Matthew McLeod, Dr Anna Jolanta Kordala, Dr Sylwia Szwec, Julia Anna Mielcarz, Dr Barbara Tedesco and Professor Angelo Poletti, bringing together the University of Milan, XYZ Laboratory, and the Cure MFM13 team as co-authors.
🌱The Story Behind This Review
The idea for this review was born over two years ago - back when Cure MFM13 (previously Cure HSPB8) did not yet exist. At that time, no comprehensive resource on HSPB8 frameshift mutations and MFM13 existed anywhere. The scientific literature was scattered, fragmented, and at times contradictory. We wanted to change that. Together with our scientific partners at XYZ Laboratory and the University of Milan, we set out to write the review we wished had existed from the beginning - one that would pull the knowledge together and make it easier for researchers and clinicians alike to understand what MFM13 is and how it works.
At the beginning of 2025, thanks to an important update in the Online Mendelian Inheritance in Man (OMIM) database, the condition was formally classified as Myofibrillar Myopathy type 13 with Rimmed Vacuoles (MFM13, OMIM:#621078). Together with that classification and this review, we are proud to be making a visible and lasting impact on how this disease is understood and recognized.
🔬What Does the Review Cover?
This is the most comprehensive resource on HSPB8 frameshift (HSPB8-fs) mutations to date, covering four key areas:
🧬HSPB8 biology and the CASA complex - how HSPB8 maintains protein quality control in muscle, heart, and nerve tissue as a core member of the Chaperone-Assisted Selective Autophagy (CASA) complex, and why its disruption is so damaging.
🧬The mutations themselves - a full catalog of all known HSPB8-fs mutations, located in the C-terminal region of the protein. Depending on the type of frameshift, the mutant protein carries either a 19-amino acid (Frame 2) or 49-amino acid (Frame 3) C-terminal extension. In silico analyses show these mutant proteins are less soluble, more aggregation-prone, and structurally abnormal. To date, in scientific literature 24 individuals across 11 families have been reported with MFM13.
🏥Clinical picture - a summary of clinical presentations across all reported cases, including progressive muscle weakness, rimmed vacuolar myopathy on biopsy, and possible respiratory, cardiac, and neurogenic involvement. The disease shows incomplete penetrance and variable expressivity, making diagnosis challenging and underscoring the need for broader genetic screening.
⚙️Pathogenic mechanisms - the review examines three key mechanisms: toxic gain of function through protein aggregation, dominant negative effect on wild-type HSPB8 and the CASA complex, and the still-debated question of haploinsufficiency. It also highlights underexplored roles of HSPB8 in mitochondrial homeostasis, stress granule dynamics, and the Integrated Stress Response.
💊Therapeutic approaches - while no approved therapies exist yet, we discuss promising candidates including autophagy-enhancing compounds (trehalose, piplartine), chemical chaperones (4-phenylbutyrate), doxycycline, and antioxidant strategies.
We hope to continue making such impactful steps towards better understanding of the disease and finding a cure.
📖Read the full review
Zhou W, Marchesi V, McLeod M, Kordala AJ, Szwec S, Mielcarz JA, Poletti A, Tedesco B. Molecular, cellular, and clinical aspects of myofibrillar myopathy caused by HSPB8 frameshift mutations. Biochim Biophys Acta Mol Basis Dis. 2026 Apr 6;1872(6):168244. doi: 10.1016/j.bbadis.2026.168244. Epub ahead of print. PMID: 41951012.
