Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare progressive genetic disease effecting one in a million individuals. During their life, patients with FOP progressively develop bone in... Show moreFibrodysplasia ossificans progressiva (FOP) is an ultra-rare progressive genetic disease effecting one in a million individuals. During their life, patients with FOP progressively develop bone in the soft tissues resulting in increasing immobility and early death. A mutation in the ACVR1 gene was identified as the causative mutation of FOP in 2006. After this, the pathophysiology of FOP has been further elucidated through the efforts of research groups worldwide. In 2015, a workshop was held to gather these groups and discuss the new challenges in FOP research. Here we present an overview and update on these topics. Show less
Osteogenesis imperfecta (OI) is characterized primarily by susceptibility to fractures with or without bone deformation. OI is genetically heterogeneous: over 20 genetic causes are recognized. We... Show moreOsteogenesis imperfecta (OI) is characterized primarily by susceptibility to fractures with or without bone deformation. OI is genetically heterogeneous: over 20 genetic causes are recognized. We identified bi-allelic pathogenic KDELR2 variants as a cause of OI in four families. KDELR2 encodes KDEL endoplasmic reticulum protein retention receptor 2, which recycles ER-resident proteins with a KDEL-like peptide from the cis-Golgi to the ER through COPI retrograde transport. Analysis of patient primary fibroblasts showed intracellular decrease of HSP47 and FKBP65 along with reduced procollagen type I in culture media. Electron microscopy identified an abnormal quality of secreted collagen fibrils with increased amount of HSP47 bound to monomeric and multimeric collagen molecules. Mapping the identified KDELR2 variants onto the crystal structure of G. gallus KDELR2 indicated that these lead to an inactive receptor resulting in impaired KDELR2-mediated Golgi-ER transport. Therefore, in KDELR2-deficient individuals, OI most likely occurs because of the inability of HSP47 to bind KDELR2 and dissociate from collagen type I. Instead, HSP47 remains bound to collagen molecules extracellularly, disrupting fiber formation. This highlights the importance of intracellular recycling of ER-resident molecular chaperones for collagen type I and bone metabolism and a crucial role of HSP47 in the KDELR2-associated pathogenic mechanism leading to OI. Show less
Mechanical stress determines bone mass and structure. It is not known whether mechanical loading affects expression of bone regulatory genes in a combined deficiency of estrogen and vitamin D. We... Show moreMechanical stress determines bone mass and structure. It is not known whether mechanical loading affects expression of bone regulatory genes in a combined deficiency of estrogen and vitamin D. We studied the effect of mechanical loading on the messenger RNA (mRNA) expression of bone regulatory genes during vitamin D and/or estrogen deficiency. We performed a single bout in vivo axial loading with 14 N peak load, 2 Hz frequency and 360 cycles in right ulnae of nineteen weeks old female control Wistar rats with or without ovariectomy (OVX), vitamin D deficiency and the combination of OVX and vitamin D deficiency (N = 10/group). Total bone RNA was isolated 6 hours after loading, and mRNA expression was detected ofMepe, Fgf23, Dmp1, Phex, Sost, Col1a1, Cyp27b1, Vdr, andEsr1. Serum levels of 25(OH)D, 1,25(OH)(2)D and estradiol were also measured at this time point. The effect of loading, vitamin D and estrogen deficiency and their interaction on bone gene expression was tested using a mixed effect model analysis. Mechanical loading significantly increased the mRNA expression ofMepe, andSost, whereas it decreased the mRNA expression ofFgf23andEsr1. Mechanical loading showed a significant interaction with vitamin D deficiency with regard to mRNA expression ofVdrandEsr1. Mechanical loading affected gene expression ofMepe, Fgf23, Sost, andEsr1independently of vitamin D or estrogen, indicating that mechanical loading may affect bone turnover even during vitamin D deficiency and after menopause. Show less
Cozijnsen, L.; Plomp, A.S.; Post, J.G.; Pals, G.; Bogunovic, N.; Yeung, K.K.; ... ; Micha, D. 2019
Background Thoracic aortic aneurysms and dissections (TAAD) may have a heritable cause in up to 20% of cases. We aimed to investigate the pathogenic effect of a TGFBR1 mutation in relation to TAAD.... Show moreBackground Thoracic aortic aneurysms and dissections (TAAD) may have a heritable cause in up to 20% of cases. We aimed to investigate the pathogenic effect of a TGFBR1 mutation in relation to TAAD. Methods Co-segregation analysis was performed followed by functional investigations, including myogenic transdifferentiation. Results The c.1043G>A TGFBR1 mutation was found in the index patient, in a deceased brother, and in five presymptomatic family members. Evidence for pathogenicity was found by the predicted damaging effect of this mutation and the co-segregation in the family. Functional analysis with myogenic transdifferentiation of dermal fibroblasts to smooth muscle-like cells, revealed increased myogenic differentiation in patient cells with the TGFBR1 mutation, shown by a higher expression of myogenic markers ACTA2, MYH11 and CNN1 compared to cells from healthy controls. Conclusion Our findings confirm the pathogenic effect of the TGFBR1 mutation in causing TAAD in Loeys-Dietz syndrome and show increased myogenic differentiation of patient fibroblasts. Show less
