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Review
. 2024 Feb 21;14(3):256.
doi: 10.3390/biom14030256.

The Dysferlinopathies Conundrum: Clinical Spectra, Disease Mechanism and Genetic Approaches for Treatments

Saeed Anwar  1 , Toshifumi Yokota  1
Affiliations
Review

The Dysferlinopathies Conundrum: Clinical Spectra, Disease Mechanism and Genetic Approaches for Treatments

Saeed Anwar et al. Biomolecules. .

Abstract

Dysferlinopathies refer to a spectrum of muscular dystrophies that cause progressive muscle weakness and degeneration. They are caused by mutations in the DYSF gene, which encodes the dysferlin protein that is crucial for repairing muscle membranes. This review delves into the clinical spectra of dysferlinopathies, their molecular mechanisms, and the spectrum of emerging therapeutic strategies. We examine the phenotypic heterogeneity of dysferlinopathies, highlighting the incomplete understanding of genotype-phenotype correlations and discussing the implications of various DYSF mutations. In addition, we explore the potential of symptomatic, pharmacological, molecular, and genetic therapies in mitigating the disease's progression. We also consider the roles of diet and metabolism in managing dysferlinopathies, as well as the impact of clinical trials on treatment paradigms. Furthermore, we examine the utility of animal models in elucidating disease mechanisms. By culminating the complexities inherent in dysferlinopathies, this write up emphasizes the need for multidisciplinary approaches, precision medicine, and extensive collaboration in research and clinical trial design to advance our understanding and treatment of these challenging disorders.

Keywords: Miyoshi myopathy; distal myopathy with anterior tibial onset (DMAT); dysferlin; dysferlinopathy; exon skipping; genetic therapy; limb-girdle muscular dystrophy recessive type 2 (LGMDR2); membrane resealing; mini-dysferlin.

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Conflict of interest statement

T.Y. is a co-founder and shareholder of OligomicsTx Inc., Calgary, AB, which aims to commercialize antisense technology. S.A. declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Exon map and phasing of human dysferlin based on the canonical transcript. Depicted is the exon (Ex) configuration of the human dysferlin gene, comprising 55 exons. Rectangles represent in-frame exons; chevron sides represent exon junctions that occur within the codons at the end of the phased exons. Above each exon, the length is annotated in base pairs (bp, purple). Beneath each, the encoded amino acid (aa, green) range is denoted. Also, the domains and binding sites (BS) for Cav3, AHNAK, and Affixin are delineated, accompanied by the respective aa range constituting each domain. The untranslated regions (UTR) at the 5′ and 3′ ends are shown in pale orange, with their base pair counts (bp, orange) inscribed within. Note: scale is indicative, not precise.
Figure 2
Figure 2
Structural overview of dysferlin protein. (A) Dysferlin, a type II transmembrane protein, is associated with various proteins important for membrane trafficking and repair. Shown is a cartoon structure view of the human dysferlin protein, predicted using the Swiss-Model protein structure prediction tool. The template for this prediction was the AlphaFold DB structure A6QQP7.1 (DYSF_BOVIN; protein sequence identity; 93.56%, coverage: 100%) corresponding to the human dysferlin sequence (GenBank protein AAC63519.1). The quality of this model was validated with Ramachandran plotting, where 92.97% of residues were found in favored regions, and only 2.26% of residues fell in outlier regions. The plasma membrane is demarcated by purple dotted lines. C2A and DysF domain sub-structures in (A) are enlarged in (B,C), respectively. (D) A simplified linear structure of human dysferlin, enumerating distinct domain functionalities [91,99]. Shown are the seven calcium-binding C2, Ferl, FerA and FerB, DysFNs and DysFCs, and transmembrane domains. Binding sites for important dysferlin partner proteins are shown as well. Dysferlin’s C2 domains have multifaceted roles: they facilitate targeting to the transverse tubules, facilitate membrane repair, modulate the amplitude of the Ca2+ transient, influence the Ca2+ transient in response to osmotic shock injury, and mitigate Ca2+ surges subsequent to such shocks [100,101]. The fer domain is known for its calcium-dependent membrane interactions 101]. The precise role of the DysF domains remains under investigation, though its mutations are frequently implicated in muscular dystrophies [89,90,91,92,93,94,95,96,97]. Note: the figures are schematic and not to scale; color coding is used for illustrative purposes only. In (D), proteins potentially interacting with dysferlin are marked with a question mark in parentheses, indicating theoretical binding regions. (Created with BioRender: US266PDI0R).
Figure 3
Figure 3
Dysferlin and its major partner proteins in the sarcolemma (simplified). This schematic illustrates dysferlin anchored to the sarcolemmal membrane, T-tubule vesicle, and intracellular vesicles. It associates with a variety of proteins, including but not limited to AHNAK, essential for membrane organization and repair; SNARE proteins, which play a pivotal role in vesicle fusion; affixin, involved in linking the actin cytoskeleton to the membrane; annexin A1 complexed with S100A10 and annexin A2 complexed with S100A11, critical for calcium-dependent membrane repair processes; calpain 3, a protease involved in muscle remodeling; caveolin 3, associated with membrane curvature and muscle fiber repair; the dihydropyridine receptor (DHPR), essential for calcium channel regulation; mitsugumin 53, involved in membrane repair; as well as α-tubulin and vinculin, which are key components of the cytoskeleton. Dysferlin’s interaction with these proteins is crucial for a range of functions from vesicle trafficking and membrane fusion to muscle contraction and calcium signaling. Note: the figure is not to scale, and color coding is used for illustrative purposes to enhance visual distinction (created with BioRender: NB266PDFC4).
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Grants and funding

No specific grant support was received for this study. T.Y. is supported by the Muscular Dystrophy Canada, the Friends of Garrett Cumming Research Fund, the HM Toupin Neurological Science Research Fund, Canadian Institutes of Health Research (CIHR), the Canada Foundation for Innovation, Alberta Advanced Education and Technology, Alberta Innovates: Health Solutions (AIHS), Jesse’s Journey, and the Women and Children’s Health Research Institute (WCHRI), The Rare Disease Foundation, and the BC Children’s Hospital Foundation. S.A. is supported by scholarships from the Maternal and Child Health (MatCH) Program, the Alberta Innovates, the Women and Children’s Health Research Institute (WCHRI), the Andrew Stewart Memorial Graduate Prizes, and the Alberta Graduate Excellence Scholarships (AGES).