Patients with Fibrodysplasia Ossificans Progressiva (FOP) suffer from ectopic bone formation, which progresses during life and results in dramatic movement restrictions. Cause of the disease are point mutations in the Activin A receptor type 1 (ACVR1), with p.R206H being most common. In this study we compared the signalling responses of ACVR1 and ACVR1 to different ligands. ACVR1, but not ACVR1 inhibited BMP signalling of BMP2 or BMP4 in a ligand binding domain independent manner. Likewise, the basal BMP signalling activity of the receptor BMPR1A or BMPR1B was inhibited by ACVR1, but enhanced by ACVR1. In comparison, BMP6 or BMP7 activated ACVR1 and caused a hyper-activation of ACVR1. These effects were dependent on an intact ligand binding domain. Finally, the neofunction of Activin A in FOP was tested and found to depend on the ligand binding domain for activating ACVR1. We conclude that the FOP mutation ACVR1 is more sensitive to a number of natural ligands. The mutant receptor apparently lost some essential inhibitory interactions with its ligands and co-receptors, thereby conferring an enhanced ligand-dependent signalling and stimulating ectopic bone formation as observed in the patients.

Oral paracoccidioidomycosis is an uncommon lesion observed in oral biopsy samples. The differences in the relative frequency of oral paracoccidioidomycosis are related to geographical variations. Men between 50 and 59 years are more affected. This study provides helpful information for clinicians in the diagnosis of oral paracoccidioidomycosis.

Collectively, these data suggest that ALDH1 immunostaining in the invasive front and in adjacent non-tumor epithelium may help identify tumors with a more aggressive behavior, potentially contributing to improving treatment customization and the monitoring of patients with head and neck cancer.

A significantly delayed DES coverage after CTO-PCI was observed. Given the known increased rate of ST following CTO-PCI and the known association between delayed DES coverage and ST, OCT may aid in determining the optimal duration of dual antiplatelet therapy after CTO-PCI.

Fibrodysplasia ossificans progressiva (FOP) is an extremely rare, autosomal dominant transmitted genetic disease. Patients experience progressive bone formation replacing tendons, ligaments, muscle and soft tissue. Cause of FOP are gain-of-function mutations in the Bone Morphogenetic Protein (BMP) receptor Activin A receptor type 1 (ACVR1) (Kaplan et al., 2008). The most common mutation is R206H, which leads to the substitution of codon 206 from arginine to histidine (Shore et al., 2006). Here, we describe the derivation and characterization of two hiPSC lines from two FOP patients, both carrying the mutation R206H. Cells were isolated from urine and reprogrammed using integration free Sendai virus vectors under defined conditions.

The euchromatic histone-lysine N-methyltransferase 1 (EHMT1) gene was examined in a 3-year-old boy with characteristic clinical features of Kleefstra syndrome. Sequencing of all 27 EHMT1 exons revealed a novel mutation, NM_024757.4:c.2712 þ 1G4A, which affects the splice donor of intron 18. Whereas the index patient is heterozygous for that mutation, his phenotypically normal mother shows tissue-specific mosaicism. Sequencing of EHMT1 RT-PCR products revealed two aberrant transcript variants: in one variant, exon 18 was skipped; in the other, a near-by GT motif was used as splice donor and intronic sequence was inserted between exons 18 and 19. Both transcript variants were found in the patient and his mother. The latter had lower amounts of these transcripts consistent with mosaic status. This is the first description of an EHMT1 point mutation being inherited from a parent with verified mosaicism. The constitutive c.2712 þ 1G4A splice site mutation in EHMT1 is fully pathogenic, and the transcript variants produced do not attenuate the severity of the disease.

Calcifying epithelial odontogenic tumor (CEOT), or Pindborg tumor, is infrequent and accounts for less than 1% of all odontogenic tumors. It is benign and usually asymptomatic but displays locally infiltrative and expansile behavior. Synchronous lesions affecting the jaws are exceedingly rare. We present a case of synchronous CEOTs affecting the maxilla and mandible and describe the clinical, radiographic, histologic, and immunohistochemical features. We further review five cases previously described in the literature.

Balanced signal transduction is crucial in tissue patterning, particularly in the vasculature. Heterotopic ossification (HO) is tightly linked to vascularization with increased vessel number in hereditary forms of HO, such as Fibrodysplasia ossificans progressiva (FOP). FOP is caused by mutations in the BMP type I receptor ACVR1 leading to aberrant SMAD1/5 signaling in response to ActivinA. Whether observed vascular phenotype in human FOP lesions is connected to aberrant ActivinA signaling is unknown. Blocking of ActivinA prevents HO in FOP mice indicating a central role of the ligand in FOP. Here, we established a new FOP endothelial cell model generated from induced pluripotent stem cells (iECs) to study ActivinA signaling. FOP iECs recapitulate pathogenic ActivinA/SMAD1/5 signaling. Whole transcriptome analysis identified ActivinA mediated activation of the BMP/NOTCH pathway exclusively in FOP iECs, which was rescued to WT transcriptional levels by the drug candidate Saracatinib. We propose that ActivinA causes transcriptional pre-patterning of the FOP endothelium, which might contribute to differential vascularity in FOP lesions compared to non-hereditary HO. Graphical abstract