Abstract Mapping holistic cell behaviors sculpting mammalian heart has been a goal, but so far only successes in transparent invertebrates and lower vertebrates. Using a live-imaging system comprising a customized vertical light-sheet microscope equipped with a culture module, a heartbeat-gated imaging strategy, and a digital image processing framework, we realized imaging of developing mouse hearts with uninterrupted cell lineages for up to 1.5 days. Four-dimensional landscapes of cell behaviors revealed a blueprint for ventricle chamber formation in which biased outward migration of outermost cardiomyocytes coupled with cell intercalation and horizontal division. The trabeculae, an inner muscle architecture, was developed through early fate segregation and transmural cell arrangement involving both oriented cell division and directional migration. Thus, live-imaging reconstruction affords a transformative means for deciphering mammalian organogenesis.
Abstract Background Cardio-facio-cutaneous (CFC) syndrome is a RASopathy subtype that presents with unique craniofacial dysmorphology, congenital heart disease, dermatologic abnormalities, growth retardation, and intellectual disability. This study describes the phenotypic spectrum of CFC in China and its association with CFC syndrome gene variants. Results Twenty Chinese CFC patients, aged 0.6–9.5 years old, were included in this study and their clinical phenotypic spectrum was compared with that of 186 patients with CFC from non-Chinese ethnicities. All 20 Chinese patients with CFC carried de novo heterozygous BRAF , MAP2K1 , and MAP2K2 variants. Two novel variants were detected and consistently predicted to be deleterious using bioinformatic tools. The clinical features of CFC in the Chinese patients included hypertrophic cardiomyopathy (2/20, 10%), pulmonary valve stenosis (2/20, 10%), curly or sparse hair (7/20, 35%), epilepsy (1/20, 5%), and hypotonia (10/20, 50%); these features were less frequently observed in Chinese patients than non-Chinese patients ( p < 0.05). In contrast, feeding difficulties (19/20, 95%) were more frequently observed in the Chinese patients. Absent eyebrows and severe short stature were more common in patients with BRAF variants than in those with MAP2K1/2 variants. Facial recognition software was used to recognize most CFC patients using artificial intelligence. Conclusion This study identified novel and common variants in our cohort of 20 Chinese patients with CFC. We uncovered differences in clinical features between Chinese and non-Chinese patients and detected genotype–phenotype correlations among the BRAF and MAP2K1/2 variant subgroups. This is the largest cohort of Chinese CFC patients to our knowledge, providing new insights into a subtype of RASopathy.
Regulators of G-protein signaling (RGS) proteins are known for the RGS domain that is composed of a conserved stretch of 120 amino acids, which binds directly to activated G-protein alpha subunits and acts as a GTPase-activating protein (GAP), leading to their deactivation and termination of downstream signals. In this study, a novel human RGS cDNA (RGS21), 1795 bp long and encoding a 152-amino acid polypeptide, was isolated by large-scale sequencing analysis of a human fetal brain cDNA library. Unlike other RGS family members, RGS21 gene has no additional domain/motif and may represent the smallest known member of RGS family. It may belong to the B/R4 subfamily, which suggests that it may serve exclusively as a negative regulator of alphai/o family members and/or alphaq/11. PCR analysis showed that RGS21 mRNA was expressed ubiquitously in the 16 tissues examined, implying general physiological roles.
Abstract Background Type II collagenopathies are a spectrum of diseases and skeletal dysplasia is one of the prominent features of collagenopathies. Molecular defects of the COL2A1 gene cause type II collagenopathies that is mainly an autosomal dominant disease, whereas some rare cases with autosomal recessive inheritance of mode have also been identified. Case presentation The patient was a 5-year-old male with a short neck, flat face, epiphyseal dysplasia, irregular vertebral endplates, and osteochondritis. Sequencing result indicated NM_001844.4: c.3662C > T; p. (Ser1221Phe) a novel missense variant, leading to a serine-to-phenylalanine substitution. Sanger sequencing confirmed the variant compared to his parents and brother. Conclusions We identified a novel homozygous variant of the COL2A1 gene as the cause of type II collagenopathies in a Chinese male, enriching the spectrum of genotypes. This is the first case of type II collagenopathies inherited in an autosomal recessive manner in China and East Asia, and it is the first case that resulted from serine substitution in the world.
Background: Short stature with optic atrophy and Pelger–Huet anomaly (SOPH; MIM 614800) syndrome is a genetic disease caused by mutation in the neuroblastoma amplified sequence (NBAS) gene. Case report: We present a 11-year-old Chinese boy with SOPH syndrome, growth hormone deficiency with a normal bone age. Gene sequencing in the patient revealed a novel compound heterozygous mutation of c.5752A > C (Thr1918Pro) and c.500_501delTT (Phe167Cysfs*7) in the NBAS gene. Conclusions: To our best knowledge, these novel mutations in the NBAS gene have not been reported. Normal bone age with growth hormone deficiency in this patient is different from the patients with SOPH syndrome that have been previously reported. These findings enrich the mutant spectrum of the NBAS gene and add our understanding of SOPH syndrome.
The precise regulation of the T-cell activation process is critical for overall immune homeostasis. Although protein phosphatase 2A (PP2A) is required for T-cell development and function, the role of PPP2CB, which is the catalytic subunit β isoform of PP2A, remains unknown. In the present study, using a T cell-specific knockout mouse of PPP2CB (PPP2CBfl/fl Lck-Cre+ ), we demonstrated that PPP2CB was dispensable for T-cell development in the thymus and peripheral lymphoid organs. Furthermore, PPP2CB deletion did not affect T-cell receptor (TCR)-induced T-cell activation or cytokine-induced T-cell responses; however, it specifically enhanced phorbol myristate acetate (PMA) plus ionomycin-induced T-cell activation with increased cellular proliferation, elevated CD69 and CD25 expression, and enhanced cytokine production (inteferon-γ, interleukin-2 and tumor necrosis factor). Mechanistic analyses suggested that the PPP2CB deletion enhanced activation of the phosphoinositide 3-kinase/Akt signaling pathway and Ca2+ flux following stimulation with PMA plus ionomycin. Moreover, the specific PI3K inhibitor rescued the augmented cell activation in PPP2CB-deficient T cells. Using mass spectrometry-based phospho-peptide analysis, we identified potential substrates of PPP2CB during PMA plus ionomycin-induced T-cell activation. Collectively, our study provides evidence of the specific role of PPP2CB in controlling PMA plus ionomycin-induced T-cell activation.
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