-
Current Opinion in Pharmacology May 2024Sarcoglycanopathies are rare autosomal recessive diseases belonging to the family of limb-girdle muscular dystrophies. They are caused by mutations in the genes coding... (Review)
Review
Sarcoglycanopathies are rare autosomal recessive diseases belonging to the family of limb-girdle muscular dystrophies. They are caused by mutations in the genes coding for α-, β-, γ-, and δ-sarcoglycan. The mutations impair the assembly of a key structural complex, which normally protects the sarcolemma of striated muscle from contraction-derived stress. Although heterogeneous, sarcoglycanopathies are characterized by progressive muscle degeneration, increased serum creatine kinase levels, loss of ambulation often during adolescence, and variable cardio-respiratory impairment. Genetic defects can impair sarcoglycan synthesis or produce a protein that is defective in folding. There is currently no effective treatment available; however, both gene replacement strategy and small molecule-based approaches show great promise and have entered or are starting to enter clinical trials.
PubMed: 38713975
DOI: 10.1016/j.coph.2024.102459 -
The Journal of Biological Chemistry Nov 2023Breast cancer stem cells are mainly responsible for poor prognosis, especially in triple-negative breast cancer (TNBC). In a previous study, we demonstrated that...
Breast cancer stem cells are mainly responsible for poor prognosis, especially in triple-negative breast cancer (TNBC). In a previous study, we demonstrated that ε-Sarcoglycan (SGCE), a type Ⅰ single-transmembrane protein, is a potential oncogene that promotes TNBC stemness by stabilizing EGFR. Here, we further found that SGCE depletion reduces breast cancer stem cells, partially through inhibiting the transcription of FGF-BP1, a secreted oncoprotein. Mechanistically, we demonstrate that SGCE could interact with the specific protein 1 transcription factor and translocate into the nucleus, which leads to an increase in the transcription of FGF-BP1, and the secreted FBF-BP1 activates FGF-FGFR signaling to promote cancer cell stemness. The novel SGCE-Sp1-FGF-BP1 axis provides novel potential candidate diagnostic markers and therapeutic targets for TNBC.
Topics: Humans; Cell Line, Tumor; Cell Proliferation; Neoplastic Stem Cells; Sarcoglycans; Signal Transduction; Sp1 Transcription Factor; Triple Negative Breast Neoplasms; Intercellular Signaling Peptides and Proteins
PubMed: 37838174
DOI: 10.1016/j.jbc.2023.105351 -
The Journal of Clinical Investigation Jun 2023Genetic testing is essential for patients with a suspected hereditary myopathy. More than 50% of patients clinically diagnosed with a myopathy carry a variant of unknown...
Genetic testing is essential for patients with a suspected hereditary myopathy. More than 50% of patients clinically diagnosed with a myopathy carry a variant of unknown significance in a myopathy gene, often leaving them without a genetic diagnosis. Limb-girdle muscular dystrophy (LGMD) type R4/2E is caused by mutations in β-sarcoglycan (SGCB). Together, β-, α-, γ-, and δ-sarcoglycan form a 4-protein transmembrane complex (SGC) that localizes to the sarcolemma. Biallelic loss-of-function mutations in any subunit can lead to LGMD. To provide functional evidence for the pathogenicity of missense variants, we performed deep mutational scanning of SGCB and assessed SGC cell surface localization for all 6,340 possible amino acid changes. Variant functional scores were bimodally distributed and perfectly predicted pathogenicity of known variants. Variants with less severe functional scores more often appeared in patients with slower disease progression, implying a relationship between variant function and disease severity. Amino acid positions intolerant to variation mapped to points of predicted SGC interactions, validated in silico structural models, and enabled accurate prediction of pathogenic variants in other SGC genes. These results will be useful for clinical interpretation of SGCB variants and improving diagnosis of LGMD; we hope they enable wider use of potentially life-saving gene therapy.
Topics: Humans; Virulence; Sarcoglycanopathies; Muscular Dystrophies, Limb-Girdle; Amino Acids
PubMed: 37317968
DOI: 10.1172/JCI168156 -
Genes Aug 2023An 8-month-old female Lagotto Romagnolo dog was presented for a 1-month history of an initial severe reluctance to move, rapidly progressing to a marked stiff gait and...
An 8-month-old female Lagotto Romagnolo dog was presented for a 1-month history of an initial severe reluctance to move, rapidly progressing to a marked stiff gait and progressive muscular weakness and evolving to tetraparesis, which persuaded the owner to request euthanasia. A primary muscle pathology was supported by necropsy and histopathological findings. Macroscopically, the muscles were moderately atrophic, except for the diaphragm and the neck muscles, which were markedly thickened. Histologically, all the skeletal muscles examined showed atrophy, hypertrophy, necrosis with calcification of the fibers, and mild fibrosis and inflammation. On immunohistochemistry, all three dystrophin domains and sarcoglycan proteins were absent. On Western blot analysis, no band was present for sarcoglycan. We sequenced the genome of the affected dog and compared the data to more than 900 control genomes of different dog breeds. Genetic analysis revealed a homozygous private protein-changing variant in the gene encoding sarcoglycan in the affected dog. The variant was predicted to induce a :p.(Leu242Pro) change in the protein. In silico tools predicted the change to be deleterious. Other 770 Lagotto Romagnolo dogs were genotyped for the variant and all found to be homozygous wild type. Based on current knowledge of gene function in other mammalian species, including humans, hamsters, and dogs, we propose the missense variant as the causative variant of the observed form of muscular dystrophy in the index case. The absence of the variant allele in the Lagotto Romagnolo breeding population indicates a rare allele that has appeared recently.
Topics: Cricetinae; Humans; Dogs; Female; Animals; Infant; Sarcoglycans; Muscular Dystrophies, Limb-Girdle; Muscle, Skeletal; Alleles; Atrophy; Mammals
PubMed: 37628692
DOI: 10.3390/genes14081641 -
Orphanet Journal of Rare Diseases Mar 2024Pathogenic missense variants in the dystrophin (DMD) gene are rarely reported in dystrophinopathies. Most DMD missense variants are of uncertain significance and their...
BACKGROUND
Pathogenic missense variants in the dystrophin (DMD) gene are rarely reported in dystrophinopathies. Most DMD missense variants are of uncertain significance and their pathogenicity interpretation remains complicated. We aimed to investigate whether DMD missense variants would cause aberrant splicing and re-interpret their pathogenicity based on mRNA and protein studies.
METHODS
Nine unrelated patients who had an elevated serum creatine kinase level with or without muscle weakness were enrolled. They underwent a detailed clinical, imaging, and pathological assessment. Routine genetic testing and muscle-derived mRNA and protein studies of dystrophin and sarcoglycan genes were performed in them.
RESULTS
Three of the 9 patients presented with a Duchenne muscular dystrophy (DMD) phenotype and the remaining 6 patients had a suspected diagnosis of Becker muscular dystrophy (BMD) or sarcoglycanopathy based on their clinical and pathological characteristics. Routine genetic testing detected only 9 predicted DMD missense variants in them, of which 6 were novel and interpreted as uncertain significance. Muscle-derived mRNA studies of sarcoglycan genes didn't reveal any aberrant transcripts in them. Dystrophin mRNA studies confirmed that 3 predicted DMD missense variants (c.2380G > C, c.4977C > G, and c.5444A > G) were in fact splicing and frameshift variants due to aberrant splicing. The 9 DMD variants were re-interpreted as pathogenic or likely pathogenic based on mRNA and protein studies. Therefore, 3 patients with DMD splicing variants and 6 patients with confirmed DMD missense variants were diagnosed with DMD and BMD, respectively.
CONCLUSION
Our study highlights the importance of muscle biopsy and aberrant splicing for clinical and genetic interpretation of uncertain DMD missense variants.
Topics: Humans; Dystrophin; Muscular Dystrophy, Duchenne; Mutation, Missense; RNA, Messenger; Sarcoglycans
PubMed: 38486238
DOI: 10.1186/s13023-024-03128-7 -
Tremor and Other Hyperkinetic Movements... 2023Epsilon-sarcoglycan (SGCE) myoclonus-dystonia is autosomal dominant (AD) with reduced penetrance due to maternal imprinting 95% of the time. Patients may lack family...
BACKGROUND
Epsilon-sarcoglycan (SGCE) myoclonus-dystonia is autosomal dominant (AD) with reduced penetrance due to maternal imprinting 95% of the time. Patients may lack family history delaying diagnosis and treatment. Additionally, counseling patients on their risk of passing on the variant differs for females versus males.
CASE REPORT
A woman in her thirties with typical phenotype of myoclonus-dystonia but lacking an AD pedigree was found to have a pathogenic variant in the SGCE gene. She was counseled that her daughters each have a 2.5% chance of expressing the phenotype.
DISCUSSION
Understanding the genetics of SGCE-myoclonus-dystonia enables effective genetic counseling and arrival at a timely diagnosis and treatment.
SUMMARY
In an era of advancing genetic analysis and precision medicine-based treatments, neurologists will be faced with increasing responsibility to properly counsel patients on the results of genetic testing. This case highlights a genetics pearl for counseling patients with epsilon-sarcoglycan myoclonus-dystonia, an autosomal dominant condition with penetrance differing by sex.
Topics: Female; Humans; Male; Dystonic Disorders; Sarcoglycans
PubMed: 37637852
DOI: 10.5334/tohm.783 -
Matrix Biology : Journal of the... May 2024Extracellular matrix (ECM) pathologic remodeling underlies many disorders, including muscular dystrophy. Tissue decellularization removes cellular components while...
The extracellular matrix differentially directs myoblast motility and differentiation in distinct forms of muscular dystrophy: Dystrophic matrices alter myoblast motility.
Extracellular matrix (ECM) pathologic remodeling underlies many disorders, including muscular dystrophy. Tissue decellularization removes cellular components while leaving behind ECM components. We generated "on-slide" decellularized tissue slices from genetically distinct dystrophic mouse models. The ECM of dystrophin- and sarcoglycan-deficient muscles had marked thrombospondin 4 deposition, while dysferlin-deficient muscle had excess decorin. Annexins A2 and A6 were present on all dystrophic decellularized ECMs, but annexin matrix deposition was excessive in dysferlin-deficient muscular dystrophy. Muscle-directed viral expression of annexin A6 resulted in annexin A6 in the ECM. C2C12 myoblasts seeded onto decellularized matrices displayed differential myoblast mobility and fusion. Dystrophin-deficient decellularized matrices inhibited myoblast mobility, while dysferlin-deficient decellularized matrices enhanced myoblast movement and differentiation. Myoblasts treated with recombinant annexin A6 increased mobility and fusion like that seen on dysferlin-deficient decellularized matrix and demonstrated upregulation of ECM and muscle cell differentiation genes. These findings demonstrate specific fibrotic signatures elicit effects on myoblast activity.
Topics: Animals; Myoblasts; Extracellular Matrix; Mice; Cell Differentiation; Sarcoglycans; Cell Movement; Dysferlin; Muscular Dystrophies; Dystrophin; Annexin A2; Decorin; Cell Line; Disease Models, Animal; Muscle, Skeletal
PubMed: 38582404
DOI: 10.1016/j.matbio.2024.04.001 -
Scientific Reports Sep 2023Sarcoglycanopathy is the most frequent form of autosomal recessive limb-girdle muscular dystrophies caused by mutations in SGCB gene encoding beta-sarcoglycan proteins....
Sarcoglycanopathy is the most frequent form of autosomal recessive limb-girdle muscular dystrophies caused by mutations in SGCB gene encoding beta-sarcoglycan proteins. In this study, we describe a shared, common haplotype co-segregating in 14 sarcoglycanopathy cases from 13 unrelated families from south Indian region with the likely pathogenic homozygous mutation c.544 T > G (p.Thr182Pro) in SGCB. Haplotype was reconstructed based on 10 polymorphic markers surrounding the c.544 T > G mutation in the cases and related family members as well as 150 unrelated controls from Indian populations using PLINK1.9. We identified haplotype H1 = G, A, G, T, G, G, A, C, T, G, T at a significantly higher frequency in cases compared to related controls and unrelated control Indian population. Upon segregation analysis within the family pedigrees, H1 is observed to co-segregate with c.544 T > G in a homozygous state in all the pedigrees of cases except one indicating a probable event of founder effect. Furthermore, Identical-by-descent and inbreeding coefficient analysis revealed relatedness among 33 new pairs of seemingly unrelated individuals from sarcoglycanopathy cohort and a higher proportion of homozygous markers, thereby indicating common ancestry. Since all these patients are from the south Indian region, we suggest this region to be a primary target of mutation screening in patients diagnosed with sarcoglycanopathy.
Topics: Humans; Asian People; Haplotypes; Mutation; Sarcoglycanopathies; Sarcoglycans
PubMed: 37699968
DOI: 10.1038/s41598-023-41487-6