Osteogenesis imperfecta (OI) is a clinically heterogeneous heritable connective tissue disorder, characterized by low bone mass and reduced strength, which result in susceptibility to fracture and bone deformities. In most cases it is caused by dominant mutations in type I collagen genes, COL1A1 and COL1A2. Recessive forms, which collectively account for approximately 5% of cases of osteogenesis imperfecta detected in North America and Europe, are caused instead by mutations in various genes coding for proteins involved in collagen posttranslational modifications, folding, and secretion. A novel disease locus, SERPINF1, coding for pigment epithelium-derived factor (PEDF), has been found recently. In SERPINF1 mutants described so far, synthesis, posttranslational modification, and secretion of type I collagen were reported to be normal. Here we describe three siblings born to consanguineous parents, who show an initially mild and then progressively worsening form of OI with severe deformities of the long bones. They are homozygous for a frameshift mutation in exon 4 of the SERPINF1 gene, which leads to lack of the transcription/translation product, likely a key factor in bone deposition and remodeling. Synthesis and secretion of type I collagen are normal. Clinical, radiographic, histological, and histomorphometric data from the proband are reminiscent of the distinctive features of type VI OI. ß
On the isolated vas deferens of the guinea-pig angiotensin potentiated strongly the height of contractions due to electrical stimulation of the hypogastric nerve; it did not affect the responses to noradrenaline and acetylcholine, nor did it elicit any contraction when given alone. Angiotensin likewise potentiated the responses ofthe cat spleen to nerve stimulation, but it also induced by itself strong contractions of the organ and reduction of the venous outflow. In experiments on the arterial blood pressure of anaesthetized and spinal cats, in which sympathetic postganglionic transmission was temporarily blocked by nicotine or tetramethylammonium, pressor responses to angiotensin were strongly reduced. As with some ganglion-stimulating drugs, the pressor responses, enhanced after a second series of nicotine injections, were reduced to the control level by hexamethonium. These findings indicate the involvement of peripheral sympathetic nerves in the action of angiotensin: the hypothesis is advanced that angiotensin acts at the peripheral nerve endings by promoting a greater output of noradrenaline.
A single grossly mutated allele (such as C41S or 555-561del) invariably leads to a condition of subclinical hypothyroidism, whereas in case of heterozygous carriers of mutations partially affecting the receptor function (such as P162A or L252P), a remarkable variable expressivity was detected among individuals belonging to different generations.
The mortality rate for malignant melanoma (MM) is very high, since it is highly invasive and resistant to chemotherapeutic treatments. The modulation of some transcription factors affects cellular processes in MM. In particular, a higher expression of the osteogenic master gene RUNX2 has been reported in melanoma cells, compared to normal melanocytes. By analyzing public databases for recurrent RUNX2 genetic and epigenetic modifications in melanoma, we found that the most common RUNX2 genetic alteration that exists in transcription upregulation is, followed by genomic amplification, nucleotide substitution and multiple changes. Additionally, altered RUNX2 is involved in unchecked pathways promoting tumor progression, Epithelial Mesenchymal Transition (EMT), and metastasis. In order to investigate further the role of RUNX2 in melanoma development and to identify a therapeutic target, we applied the CRISPR/Cas9 technique to explore the role of the RUNT domain of RUNX2 in a melanoma cell line. RUNT-deleted cells showed reduced proliferation, increased apoptosis, and reduced EMT features, suggesting the involvement of the RUNT domain in different pathways. In addition, del-RUNT cells showed a downregulation of genes involved in migration ability. In an in vivo zebrafish model, we observed that wild-type melanoma cells migrated in 81% of transplanted fishes, while del-RUNT cells migrated in 58%. All these findings strongly suggest the involvement of the RUNT domain in melanoma metastasis and cell migration and indicate RUNX2 as a prospective target in MM therapy.
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