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Collagen VI exerts several functions in the tissues in which it is expressed, including mechanical roles, cytoprotective functions with the inhibition of apoptosis and oxidative damage, and the promotion of tumor growth and progression by the regulation of cell differentiation and autophagic mechanisms. Mutations in the genes encoding collagen VI main chains, COL6A1, COL6A2 and COL6A3, are responsible for a spectrum of congenital muscular disorders, namely Ullrich congenital muscular dystrophy (UCMD), Bethlem myopathy (BM) and myosclerosis myopathy (MM), which show a variable combination of muscle wasting and weakness, joint contractures, distal laxity, and respiratory compromise. No effective therapeutic strategy is available so far for these diseases; moreover, the effects of collagen VI mutations on other tissues is poorly investigated. The aim of this review is to outline the role of collagen VI in the musculoskeletal system and to give an update about the tissue-specific functions revealed by studies on animal models and from patients’ derived samples in order to fill the knowledge gap between scientists and the clinicians who daily manage patients affected by collagen VI-related myopathies.

BackgroundFibrillinopathies comprise allelic disorders with opposing phenotypes. Pathogenic variants in fibrillin-2, encoded by FBN2, have mainly been associated with congenital contractural arachnodactyly but in a few cases also with brachydactyly.Methods and resultsWe recruited two families with index patients presenting with short stature (heights ≤3 SD scores), brachydactyly, joint contractures and facial dysmorphism as major features. In Family 2, the proband and father also had carpal tunnel syndrome. Radiographs showed signs of mild skeletal dysplasia with short long bones, brachydactyly and mild metaphyseal and vertebral irregularity. Whole genome sequencing revealed novel variants in the FBN2 gene that segregated with the phenotype: in Family 1, a novel heterozygous missense variant c.4862G>A, p.(Cys1621Tyr) and in Family 2, a novel heterozygous deletion of exons 9–11. The missense variant affects a highly conserved residue and is predicted to be deleterious by most in silico tools. The FBN2 deletion affects a well-conserved region and leads to loss of the transforming growth factor β binding-like 2 domain and part of the calcium-binding epidermal growth factor-like domain.ConclusionOur findings suggest that short stature and mild skeletal dysplasia might be part of the spectrum of FBN2-related phenotypes. The study supports the role of FBN2 variants in growth failure and expands the molecular spectrum of FBN2 variants.

Abstract Dupuytren's disease is characterized by fingers becoming permanently bent in a flexed position. Whereas people of African ancestry are rarely afflicted by Dupuytren's disease, up to ∼30% of men over 60 years suffer from this condition in northern Europe. Here, we meta-analyze 3 biobanks comprising 7,871 cases and 645,880 controls and find 61 genome-wide significant variants associated with Dupuytren's disease. We show that 3 of the 61 loci harbor alleles of Neandertal origin, including the second and third most strongly associated ones (P = 6.4 × 10−132 and P = 9.2 × 10−69, respectively). For the most strongly associated Neandertal variant, we identify EPDR1 as the causal gene. Dupuytren's disease is an example of how admixture with Neandertals has shaped regional differences in disease prevalence.

Fibrosis is characterized by excessive matrix protein accumulation and contributes to significant morbidity and mortality in the Western world. The relative lack of effective antifibrotic therapeutics for the majority of these conditions reflects the difficulty in identifying targets for human fibrosis. Animal models fail to recapitulate all of the facets of human disease, and the limited clinical samples from patients with fibrosis of visceral organs are usually of late-stage disease [J. Nanchahal, B. Hinz, Proc. Natl. Acad. Sci. U.S.A. 113, 7291–7293 (2016)]. Here, we use Dupuytren’s disease (DD), a localized fibrotic condition of the hand, as a model to profile the vasculature niche of human fibrosis at single-cell resolution. Our spatially resolved molecular taxonomy of fibrotic blood vessels identifies distinct endothelial and pericyte populations and demonstrates a complex topological organization in the fibrotic microenvironment. In developing fibrosis, we show that the endothelium acts to promote immune regulatory fibroblast phenotype through platelet-derived growth factor (PDGF) signaling, thereby sustaining an immune cell–enriched perivascular niche. Moreover, we highlight pericytes as “housing” a putative myofibroblast precursor in DD. Overall, our results elucidate a tightly coupled vasculature niche in fibrosis that instructs the differentiation of functionally distinct stromal cells. These findings provide an important translational resource and highlight the therapeutic potential of targeting blood vessel signaling in human fibrosis.

Dupuytren disease (DD), a fibroproliferative disorder of the palmar fascia that causes flexion contractures in the fingers, is prevalent in people of North-Western European descent and less so in other ethnicities. DD is a complex disorder, influenced by genetic risk variants. We aimed to study if the marked differences in prevalences in DD between ethnic (sub)groups could be explained by differences in allele frequencies of the 26 known genetic risk variants of DD. Therefore, genetic risk scores (GRS) composed of the 26 DD risk variants were calculated for the 26 populations from the 1000 Genomes database and correlated to observed DD prevalences from literature. For comparison, GRSs were generated for 10,000 sets of 26 random SNPs and also correlated to the observed DD prevalences to determine the significance of the observed correlation. To determine whether differences in allele frequencies between ethnicities were caused by natural selection, fixation indices (Fst) were calculated from the 26 SNPs and from the sets of 26 random SNPs for comparison. Observed prevalences could be determined from literature for 10 populations. Their correlation with the GRS composed of DD SNPs proved to be 0.60 (p = 0.0003). The Fsts between British and other populations were low for European, ad mixed American, and South-Asian populations, and moderate for East-Asians. African populations were significantly different from expected values determined from the random sets. In conclusion, the 26 known genetic risk variants associated with DD explain for a substantial part (R2 = 0.36) the differing DD prevalences observed between ethnicities.

Dupuytren’s disease (DD) is a highly heritable fibrotic disorder of the hand with incompletely understood etiology. A number of genetic loci, including Wnt signaling members, have been previously identified. Our overall aim was to identify novel genetic loci, to prioritize genes within the loci for functional studies, and to assess genetic correlation with associated disorders. We performed a meta-analysis of six DD genome-wide association studies from three European countries and extensive bioinformatic follow-up analyses. Leveraging 11,320 cases and 47,023 controls, we identified 85 genome-wide significant single nucleotide polymorphisms in 56 loci, of which 11 were novel, explaining 13.3–38.1% of disease variance. Gene prioritization implicated the Hedgehog and Notch signaling pathways. We also identified a significant genetic correlation with frozen shoulder. The pathways identified highlight the potential for new therapeutic targets and provide a basis for additional mechanistic studies for a common disorder that can severely impact hand function. In this meta-analysis of the fibrotic hand disorder Dupuytren’s disease, the authors identify genetic risk variants, study them for their functional consequences and implicate two signaling pathways involved in the disease mechanism of this debilitating disorder.

Fibrosis is a common and integral pathological feature in various chronic diseases, capable of affecting any tissue or organ. Fibrosis within deep fascia is implicated in many myofascial disorders, including gluteal muscle contracture (GMC), Dupuytren’s disease, plantar fasciitis, iliotibial band syndrome, and chronic muscle pain. Despite its clinical significance, deep fascia fibrosis remains considerably under-researched compared to other fibrotic conditions. Single-cell RNA-sequencing (scRNA-seq) has been used to investigate cellular heterogeneity in fibrotic tissues. However, to our knowledge, only a few studies have applied scRNA-seq to explore cellular heterogeneity in deep fascia, and none have specifically examined fibrotic fascia. In this study, we performed scRNA-seq analysis on fibrotic fascia associated with GMC and compared them to nonfibrotic control fascial samples. Our findings show that fibroblast and macrophage cells play critical roles in pathological tissue remodeling within fibrotic deep fascia. We observed an upregulation of various collagens, proteoglycans, and extracellular matrix (ECM) glycoproteins in contracture deep fascia, attributed to the widespread activation of fibroblast subclusters. Additionally, two pro-fibrotic macrophage subpopulations, SPP1 + MP and ECM-like MP, appear to facilitate ECM deposition in fibrotic deep fascia by either regulating fibroblast activation or directly contributing to ECM production. The SPP1 + MP and ECM-like MP cells, as well as the signal interaction between SPP1 + MP and fibroblast cells, present potential therapeutic target for treating GMC and other related myofascial disorders.

Poikiloderma with tendon contracture, myopathy and pulmonary fibrosis (POIKTMP) is a rare hereditary disorder caused by mutations in the FAM111B gene, characterised by multi‐organ fibrosis, particularly affecting the lungs. This study investigates the molecular mechanisms of fibrosis in POIKTMP through genotyping and gene expression profiling of FAM111B and associated fibrotic pathways. Post‐mortem formalin‐fixed paraffin‐embedded (FFPE) tissues from a POIKTMP patient and healthy controls were analysed. Genomic DNA was extracted, confirming the FAM111B Y621D mutation via Sanger sequencing. RT‐qPCR and the RT2 Profiler PCR Array were used to evaluate fibrosis‐related gene expression in lung and skin tissues. Disease and pathway enrichment analyses were conducted using Metascape, GeneMANIA and Enrichr tools. The FAM111B Y621D mutation was validated, and gene expression profiling revealed significant upregulation of fibrotic markers, such as TGFβ‐3, PDGFA, ITGB1, MMP3, MMP13 and CCN2 in the lungs, and COL3A1 and THBS2 in the skin. Pathway enrichment analysis linked FAM111B to extracellular matrix remodelling, cell adhesion, and cancer. These findings suggest that FAM111B mutations drive fibrosis through dysregulated gene networks, highlighting potential therapeutic targets for POIKTMP and related fibrotic diseases. Further research is required to understand FAM111B's role in fibrosis fully.

Purpose Congenital contractural arachnodactyly (CCA) is an autosomal dominant connective tissue disorder manifesting joint contractures, arachnodactyly, crumpled ears, and kyphoscoliosis as main features. Due to its rarity, rather aspecific clinical presentation, and overlap with other conditions including Marfan syndrome, the diagnosis is challenging, but important for prognosis and clinical management. CCA is caused by pathogenic variants in FBN2 , encoding fibrillin-2, but locus heterogeneity has been suggested. We designed a clinical scoring system and diagnostic criteria to support the diagnostic process and guide molecular genetic testing. Methods In this retrospective study, we assessed 167 probands referred for FBN2 analysis and classified them into a FBN2 -positive ( n  = 44) and FBN2 -negative group ( n  = 123) following molecular analysis. We developed a 20-point weighted clinical scoring system based on the prevalence of ten main clinical characteristics of CCA in both groups. Results The total score was significantly different between the groups ( P  < 0.001) and was indicative for classifying patients into unlikely CCA (total score <7) and likely CCA (total score ≥7) groups. Conclusions Our clinical score is helpful for clinical guidance for patients suspected to have CCA, and provides a quantitative tool for phenotyping in research settings.

H syndrome, a rare autosomal recessive disorder, is caused by pathogenic variants in the SLC29A3 gene located on chromosome 10q22. The clinical phenotype encompasses diverse manifestations, including hyperpigmentation, hypertrichosis, hepatosplenomegaly, hearing loss, heart anomalies, hypogonadism, short stature, hyperglycemia with insulin-dependent diabetes mellitus, and hallux valgus/flexion contractures. A 20-year-old Syrian male born to consanguineous parents presented with fever, productive cough, chest pain, dyspnea, and scrotal discomfort. His medical history included progressive bilateral sensorineural hearing loss, failure to thrive, and significant short stature (height 1.46 m and weight 44 kg). Physical examination revealed conjunctival pallor, icterus, jugular vein distention, hypertrichosis, hypoplastic genitalia, and decreased breath sounds and dullness to percussion that were consistent with pneumonia and pleural effusion. Hormonal evaluation indicated primary hypogonadism and growth hormone deficiency. Echocardiography revealed pulmonary hypertension and tricuspid valve insufficiency. Chest imaging confirmed bilateral pleural effusion and lung infiltrates. The constellation of clinical findings, including hypogonadism, hypertrichosis, hallux valgus, and hepatosplenomegaly, collectively suggested H syndrome. The patient received supplemental oxygen therapy, resulting in improved oxygen saturation. Empirical antibiotic therapy consisting of intravenous ceftriaxone and levofloxacin was administered for 10 days, resulting in clinical improvement and resolution of respiratory symptoms. Given the high prevalence of this condition among consanguineous populations within resource-limited settings, this report emphasizes the critical need for accessible genetic testing and heightened clinical awareness of this rare disorder.