Kathryn Byerly

Mitral valve prolapse (MVP) is a common congenital valve disorder that has been linked to defects in primary cilia during cardiac development, yet the mechanisms connecting ciliary regulation to valvulogenesis remain incompletely understood. As DZIP1 is required for ciliogenesis and has been shown to be involved in MVP pathogenesis, we sought to identify interacting partners that may regulate its localization and function. Using an unbiased yeast two-hybrid screen of a human heart cDNA library, we identified BRD10, a previously uncharacterized bromodomain-containing protein, as a DZIP1-interacting partner. Co-immunoprecipitation confirmed the DZIP1–BRD10 interaction and mapped the binding region to a conserved domain containing a putative nuclear localization sequence. RNAscope and immunofluorescence demonstrated that BRD10 and DZIP1 are co-expressed in developing murine valve cells, with BRD10 localizing near the basal body and transition zone of the primary cilium. BRD10 also interacted with acetylated α-tubulin, supporting a relationship with ciliary microtubule structures. Nuclear–cytoplasmic fractionation further showed that BRD10 promotes cytoplasmic enrichment of DZIP1. Together, these findings identify BRD10 as a novel regulator of DZIP1 subcellular localization and suggest that bromodomain-mediated recruitment at the primary cilium may contribute to normal valvulogenesis and developmental mechanisms relevant to MVP.

Background/Objectives: Dermatosparaxis Ehlers–Danlos syndrome (dEDS) is a rare autosomal recessive connective tissue disorder caused by biallelic pathogenic variants in ADAMTS2, which encodes the primary N-proteinase responsible for fibrillar procollagen processing. Although defective procollagen cleavage is the defining molecular feature of dEDS, how ADAMTS2 deficiency disrupts extracellular matrix (ECM) organization and tissue integrity remains incompletely understood. Here we characterized the structural, molecular, and cellular consequences of a knock-in Adamts2 mouse model harboring a disease-associated variant and assessed its phenotypic and mechanistic resemblance to human dEDS. Methods: We generated Adamts2^Q226* mice carrying a variant analogous to a human dEDS-causing mutation. Skin from homozygous, heterozygous, and control animals was evaluated using histologic, ultrastructural, biochemical, digital pathology, and single-nucleus RNA-sequencing approaches. Pathway enrichment analyses and the computational tool CellChat were used to infer altered molecular programs and changes in intercellular communication. Results: Homozygous knock-in mice exhibited near-complete loss of dermal ADAMTS2 protein expression, impaired type I procollagen processing, disrupted dermal architecture, and irregular hieroglyphic collagen fibrils characteristic of dEDS. Digital pathology demonstrated reduced collagen bulk, diminished assembled and total collagen, increased fine collagen, and loss of mature collagen architecture, with intermediate changes in heterozygous animals. Single-nucleus RNA sequencing identified fibroblasts as the most affected population, with coordinated downregulation of collagen, microfibrillar, and other ECM-associated genes. Pathway analyses implicated altered ECM organization, receptor-linked signaling, cytoskeletal regulation, protein processing, and metabolism, while CellChat inferred widespread reductions in intercellular communication. Conclusions: ADAMTS2 deficiency causes fibroblast-enriched transcriptional remodeling, impaired collagen processing and ECM maturation, and disrupted tissue-wide cellular communication. This model provides a translational platform for studying dEDS pathogenesis and strategies to restore ECM homeostasis.

Van Maldergem Syndrome (VMS) is a rare autosomal recessive disorder caused by pathogenic variants in the atypical cadherin genes DCHS1 or FAT4 and is marked by craniofacial, skeletal, and neurodevelopmental abnormalities. Although DCHS1–FAT4 binding is mediated by their respective extracellular domains, the in vivo function of the DCHS1 intracellular domain (ICD) is poorly defined. To test its function, we generated mice in which the DCHS1 ICD was deleted and replaced with a V5 epitope tag (Dchs1^ΔICD-V5). Homozygous Dchs1^{ΔICD-V5/ΔICD-V5} mice are viable but exhibit VMS-like craniofacial flattening with enlarged fontanelles and reduced palatine/maxillary structures, along with airway cartilage abnormalities including reduced mineralization and decreased tracheal circularity. In periventricular regions, wild-type DCHS1 expression shows polarized localization, whereas mice with the ICD deletion exhibit altered cell polarization within the subventricular zone, concomitant with changes in neural cellular distribution. Neonatal brains display reduced pYAP1: YAP1 ratios and increased Ki67+ proliferation with greater Ki67–neuronal co-localization within the periventricular zone. Together, these data identify the DCHS1 ICD as a critical effector for DCHS1 signaling and a regulator of polarity-dependent growth, with associated changes in Hippo pathway activity during craniofacial and neural morphogenesis. Additionally, our data establish Dchs1^{ΔICD-V5/ΔICD-V5} mice as a model that recapitulates core features of VMS, thereby allowing new mechanistic discoveries into its pathogenesis.

Recent evidence demonstrates that mitral valve prolapse (MVP) increases mechanical stress on the subvalvular apparatus and is linked to regional myocardial fibrosis and life-threatening ventricular arrhythmias. However, current surgical guidelines do not account for the extent of myocardial fibrosis or the severity of leaflet involvement, both key features of arrhythmogenic MVP. To address this gap, we conducted histopathological analysis of endomyocardial biopsies from patients with MVP and regionalized myocardial fibrosis (n = 6) who underwent mitral valve repair. Using digital pathology-based quantitative image analysis (QIA), we found that fibrosis in peri-papillary biopsies exhibited a significantly higher Morphometric Composite Score compared with remote biopsies (5.68 ± 0.69 vs. 3.71 ± 0.49, p = 0.042), reflecting larger, more branched, and more assembled collagen fibers, indicative of a mature and persistent fibrotic phenotype. These findings suggest that myocardial scarring in MVP is well-established by the time of surgery and underscore the potential value of earlier surgical intervention to reduce the risk of arrhythmia and preserve post-operative left ventricular function.

Background: Hypermobile Ehlers–Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSDs) are prevalent, complex conditions marked by chronic pain, joint instability, and multisystem involvement. Despite affecting an estimated 1 in 500 individuals, these conditions remain poorly understood and inconsistently diagnosed. This study aimed to define their clinical burden through a large-scale, international survey. Methods: A cross-sectional, anonymous survey was distributed globally from September 2023 to March 2024. Of 9258 responses, 3906 met inclusion criteria (hEDS: n = 3360; HSD: n = 546). The 418-item questionnaire assessed symptoms, comorbidities, healthcare utilization, and quality of life. The 95% confidence intervals (CIs) were calculated for comparison. Results: Participants with hEDS reported a mean of 24 comorbid conditions and an average diagnostic delay of 22.1 years. Common diagnoses included gastrointestinal disorders (84.3% [95% CI: 98.3–99.2%]), dysautonomia (71.4% [95% CI: 69.9–72.9%]), and chronic pain (98.9% [95% CI: 98.3–99.2%]). In contrast, HSD respondents reported a mean of 17 comorbidities, a 17.5-year time to diagnosis, and lower rates of key complications. Triggering events, such as puberty and infections were commonly reported preceding hEDS or HSD symptom onset. Comparison to the All of Us dataset revealed significantly elevated prevalence ratios of neurological, immune, and autonomic diagnoses. Conclusions: This global survey highlights the extensive multisystemic burden and diagnostic delays faced by individuals with hEDS and HSDs. The high prevalence of immune, neurological, gastrointestinal, and autonomic dysfunctions challenges the notion of these conditions as isolated connective tissue disorders. These findings highlight the need for updated diagnostic frameworks and mechanistic studies that explore multifactorial etiologies beyond the connective tissue paradigm.

Intercellular interactions among cardiac cell populations are essential for cardiac morphogenesis, yet the molecular mechanisms orchestrating these events remain incompletely understood. Dachsous1 (Dchs1), an atypical cadherin linked to mitral valve prolapse, is a core planar cell polarity protein whose function in the developing heart has not been fully elucidated. To address this, we generated a Dchs1-HA knock-in mouse model to define its spatial, temporal, and cellular expression patterns. Using immunohistochemistry, western blotting, and single-cell transcriptomics across developmental stages, we demonstrate that cardiac Dchs1 expression is restricted to non-cardiomyocyte lineages. DCHS1 displays dynamic subcellular localization and tissue organization depending on the developmental timepoint, with staining being found in epicardial and endocardial surfaces at earlier embryonic stages and in the compact myocardium in later fetal and neonatal stages. During fetal and neonatal stages, DCHS1-positive non-myocyte, non-endothelial cells form polarized extensions that bridge endothelial and non-myocyte, non-endothelial cells, suggesting direct heterotypic and homotypic interactions. Western blotting revealed evidence of DCHS1 proteolytic cleavage, with intracellular C-terminal fragments. RNA co-expression with its binding partner FAT4 supports a conserved, non-myocyte-specific DCHS1-FAT4 signaling axis. These findings identify DCHS1 as a potential molecular tether that is utilized in intercellular communications during cardiac development, with implications for congenital and acquired heart disease.

Soil sulfur metabolism surprise: Soil bacteria have a range of metabolic pathways that contribute to acquiring and recycling nutrients and carbon. Curiously, some of these organisms give off ethylene gas when starved for sulfur under anaerobic conditions. North et al. traced the source of ethylene to a small, sulfur-containing organic molecule produced by certain reactions in cells. Growing cells in sulfur-limiting conditions enabled them to identify the enzymes involved in sulfur salvage, and the concomitant ethylene production, through this pathway. Methane and ethane were also observed as products when appropriate substrates were provided. The key genes involved are distantly related to nitrogenase and several other reductase enzymes found in bacteria and archaea. The involvement of such nitrogenase-like genes in sulfur metabolism highlights the potential of unexplored diversity in this family of enzymes and raises many mechanistic and evolutionary questions that are now ripe for exploration. Science , this issue p. 1094