APJ+ cells in the SHF contribute to the cells of aorta and pulmonary trunk through APJ signaling.

Outflow tract (OFT) develops from cardiac progenitor cells in the second heart field (SHF) domain. APJ, a G-Protein Coupled Receptor, is expressed by cardiac progenitors in the SHF. By lineage tracing APJ+SHF cells, we show that these cardiac progenitors contribute to the cells of OFT, which eventually give rise to aorta and pulmonary trunk/artery upon its morphogenesis. Furthermore, we show that early APJ â€‹+ â€‹cells give rise to both aorta and pulmonary cells but late APJ â€‹+ â€‹cells predominantly give rise to pulmonary cells. APJ is expressed by the outflow tract progenitors in the SHF but its role is unclear. We performed knockout studies to determine the role of APJ in SHF cell proliferation and survival. Our data suggested that APJ knockout in the SHF reduced the proliferation of SHF progenitors, while there was no significant impact on survival. In addition, we show that ectopic overexpression of WNT in these cells disrupted aorta and pulmonary morphogenesis from OFT. Overall, our study has identified APJ â€‹+ â€‹progenitor population within the SHF that give rise to aorta and pulmonary trunk/artery cells. Furthermore, we show that APJ signaling stimulates proliferation of these cells in the SHF.

SSR4-CDG, an ultra-rare X-linked congenital disorder of glycosylation affecting the TRAP complex: Review of 22 affected individuals including the first adult patient.

Congenital disorders of glycosylation (CDG) are a group of rare, often multi-systemic genetic disorders that result from disturbed protein and lipid glycosylation. SSR4-CDG is an ultra-rare, comparably mild subtype of CDG, presenting mostly in males. It is caused by pathogenic variants in the SSR4 gene, which is located on the X chromosome. SSR4 (signal sequence receptor protein 4) is a subunit of the translocon-associated protein (TRAP) complex, a structure that is needed for the translocation of proteins across the ER membrane. A deficiency of SSR4 leads to disturbed N-linked glycosylation of proteins in the endoplasmic reticulum. Here, we review the most common clinical, biochemical and genetic features of 18 previously published individuals and report four new cases diagnosed with SSR4-CDG, including the first adult affected by this disorder. Based on our review, developmental delay, speech delay, intellectual disability, muscular hypotonia, microcephaly and distinct facial features are key symptoms of SSR4-CDG that are present in all affected individuals. Although these symptoms overlap with many other neurodevelopmental disorders, their combination with additional clinical features, and a quite distinguishable facial appearance of affected individuals make this disorder a potentially recognizable type of CDG. Additional signs and symptoms include failure to thrive, feeding difficulties, connective tissue involvement, gastrointestinal problems, skeletal abnormalities, seizures and, in some cases, significant behavioral abnormalities. Due to lack of awareness of this rare disorder, and since biochemical testing can be normal in affected individuals, most are diagnosed through genetic studies, such as whole exome sequencing. With this article, we expand the phenotype of SSR4-CDG to include cardiac symptoms, laryngeal abnormalities, and teleangiectasia. We also provide insights into the prognosis into early adulthood and offer recommendations for adequate management and care. We emphasize the great need for causal therapies, as well as effective symptomatic therapies addressing the multitude of symptoms in this disease. In particular, behavioral problems can severely affect quality of life in individuals diagnosed with SSR4-CDG and need special attention. Finally, we aim to improve guidance and education for affected families and treating physicians and create a basis for future research in this disorder.

Frontiers in congenital disorders of glycosylation consortium, a cross-sectional study report at year 5 of 280 individuals in the natural history cohort.

OBJECTIVE: Our report describes clinical, genetic, and biochemical features of participants with a molecularly confirmed congenital disorder of glycosylation (CDG) enrolled in the Frontiers in Congenital Disorders of Glycosylation (FCDGC) Natural History cohort at year 5 of the study. METHODS: We enrolled individuals with a known or suspected CDG into the FCDGC Natural History Study, a multicenter prospective and retrospective natural history study of all genetic causes of CDG. We conducted a cross-sectional analysis of baseline study visit data from participants with confirmed CDG who were consented into the FCDGC Natural History Study (5U54NS115198) from October 2019 to November 2023. RESULTS: Three hundred thirty-three subjects consented to the FCDGC Natural History Study. Of these, 280 unique individuals had genetic data available that was consistent with a diagnosis of CDG. These 280 individuals were enrolled into the study between October 8, 2019 and November 29, 2023. One hundred forty-one (50.4%) were female, and 139 (49.6%) were male. Mean and median age at enrollment was 10.1 and 6.5 years, respectively, with a range of 0.22 to 71.4 years. The cohort encompassed individuals with disorders of N-linked protein glycosylation (57%), glycosylphosphatidylinositol anchor disorder (GPI anchor) (15%), disorders of Golgi homeostasis, trafficking and transport (12%), dolichol metabolism disorders (5%), disorders of multiple pathways (6%), and other (5%). The most frequent presenting symptom(s) leading to diagnosis were developmental delay/disability (77%), followed by hypotonia (56%) and feeding difficulties (42%). Mean and median time between first related symptom and diagnosis was 2.7 and 0.8 years, respectively. One hundred percent of individuals in our cohort had developmental differences/disabilities at the time of their baseline visit, followed by 97% with neurologic involvement, 91% with gastrointestinal (GI)/liver involvement, and 88% with musculoskeletal involvement. Severity of disease in individuals was scored on the Nijmegen Progression CDG Rating Scale (NPCRS) with 27% of scores categorized as mild, 44% moderate, and 29% severe. Of the individuals with N-linked protein glycosylation defects, 83% of those with data showed a type 1 pattern on carbohydrate deficient transferrin (CDT) analysis including 82/84 individuals with PMM2-CDG, 6% a type 2 pattern, 1% both type 1 and type 2 pattern and 10% a normal or nonspecific pattern. One hundred percent of individuals with Golgi homeostasis and trafficking defects with data showed a type 2 pattern on CDT analysis, while Golgi transport defect showed a type II pattern 73% of the time, a type 1 pattern for 7%, and 20% had a normal or nonspecific pattern. Most of the variants documented were classified as pathogenic or likely pathogenic using ACMG criteria. For the majority of the variants, the predicted molecular consequence was missense followed by nonsense and splice site, and the majority of the diagnoses are inherited in an autosomal recessive pattern but with disorders of all major nuclear inheritance included. DISCUSSION: The FCDGC Natural History Study serves as an important resource to build future research studies, improve clinical care, and prepare for clinical trial readiness. Herein is the first overview of CDG participants of the FCDGC Natural History Study.

APJ expression is lost in isolated embryonic coronary endothelial cell culture in vitro.

Coronary artery disease is one of the leading causes of death worldwide, and yet we lack the appropriate therapeutic treatments for it. Investigation into the mechanisms of coronary vessel development can provide insights into potential therapies to repair and regenerate damaged coronary arteries. Our previous study in the mouse embryo have implicated APJ, a G-protein coupled receptor that is expressed by coronary endothelial cells in vivo, to be an important regulator of coronary vessel development. In this study, we report an unexpected finding that the isolated embryonic coronary endothelial cells lose APJ expression in culture in vitro.

Hypoxia regulate developmental coronary angiogenesis potentially through VEGFR2- and SOX17-mediated signaling.

Background: Coronary vessels in embryonic mouse heart arises from multiple progenitor population including sinus venosus (SV), endocardium, and proepicardium. ELA/APJ signaling is shown to regulate coronary growth from SV pathway within the subepicardium, whereas VEGF-A/VEGF-R2 pathways is implicated to regulate coronary growth from endocardium pathway. Our previous study show hypoxia as a potential signaling cue to stimulate overall coronary growth and expansion within the myocardium. However, the role of hypoxia and its downstream signaling pathways in the regulation of coronary vessel development is not known. In this study, we investigated the role of hypoxia in coronary vessel development and have identified SOX17- and VEGF-R2-mediated signaling as a potential downstream pathway of hypoxia in the regulation of coronary vessel development. Results: We show that hypoxia gain-of-function in the myocardium through upregulation of HIF-1α disrupts the normal pattern of coronary angiogenesis in developing mouse hearts and displays phenotype that is reminiscent of accelerated coronary growth. We show that VEGF-R2 expression is increased in coronary endothelial cells under hypoxia gain-of-function in vivo and in vitro . Furthermore, we show that SOX17 expression is upregulated in developing mouse heart under hypoxia gain-of-function conditions, whereas SOX17 expression is repressed under hypoxia loss-of-function conditions. Furthermore, our results show that SOX17 loss-of-function disrupts normal pattern of coronary growth. Conclusion: Collectively, our data provide strong phenotypic evidence to show that hypoxia might regulate coronary growth in the developing mouse heart potentially through VEGF-R2- and SOX17-mediated downstream signaling pathways.