| 2016 | Severe osteoporosis with multiple spontaneous vertebral fractures in a young male carrying triple polymorphisms in the vitamin D receptor, collagen type 1, and low-density lipoprotein receptor-related peptide 5 genes. | Hormones (Athens) | Osteoporosis is a common disease with a strong genetic component. Several studies have reported the vitamin D receptor (VDR), collagen type I (COL1A1), and LDL receptor-related protein 5 (LRP5) genes as the most likely candidates. However, most of the studies have been carried out in postmenopausal women and older men and show inconsistent results.We report a case of a 26-year old male who presented with severe back pain of acute onset, unrelated to any kind of trauma, and diffuse myalgia. Imaging of the lumbar and the thoracic spine revealed two Grade 3, according to Genant's semiquantitative method, vertebral fractures in T10 and T11 and multiple Grade 1 and 2 fractures from T8 to L2. Measurement of bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA) (Lunar Prodigy) showed severe osteoporosis of the lumbar spine (Z-score=-3.0, BMD = 0.866 gr/cm2). A complete laboratory and biochemical work-up was performed to exclude secondary causes of osteoporosis. Total genomic DNA was extracted from peripheral blood and was used as a template for genotype analysis. The patient was heterozygous for the p.V667M mutation of the LRP5 gene and for the BsmI [g.63980 G→A, rs1544410] and Sp1 polymorphisms [g.6252 G→T, rs1800012] of the VDR and COL1A1 genes, respectively. Further genotype analysis excluded types of osteogenesis imperfecta associated with mutations in the COL1A1 and COL1A2 genes.We herein show that the co-existence of three polymorphic sites in the VDR, COL1A1, and LPR-5 genes in a young male adult caused severe osteoporosis with multiple fractures, suggesting a combined effect and/or interaction between these genes. |
| 1997 | Increased activity of the alpha 1(I) procollagen promoter in skin fibroblasts from patients with chronic eosinophilia-myalgia syndrome. | Int J Biochem Cell Biol | Eosinophilia-myalgia syndrome (EMS), a novel L-tryptophan-associated disease, which occurred as an epidemic in 1989, is characterized by diffuse fibrosis of the skin. The objective of these studies was to compare the in vitro expression of the gene encoding the human alpha 1(I) procollagen (COL1A1) in dermal fibroblasts derived from patients with long-standing EMS and from healthy controls. Early passage fibroblasts in culture were transiently transfected with a series of progressively 5' deleted human COL1A1 promoter-CAT reporter gene DNA constructs. Resultant CAT activity was assayed in the cytoplasmic extracts. Following transient transfection, COL1A1 promoter activity in 4/5 fibroblast cell lines derived from patients with EMS was two-to threefold greater than in matched normal fibroblasts. Deletion analysis indicated that CAT activity was highest, and displayed the greatest increase in EMS vs normal fibroblasts, with promoter constructs spanning 174 bp upstream from the COL1A1 transcription start site. The study shows increased CAT activity driven by a 174 bp fragment of COL1A1 in transiently transfected skin fibroblasts from patients with EMS even in the chronic stage of disease. These findings expand on previous observations indicating increased type I collagen gene expression in EMS fibroblasts, and suggest that fibrosis in L-tryptophan-induced EMS is associated with transcriptional activation of type I collagen gene expression, which persists even following cessation of L-tryptophan use. |
| 1993 | Increased type I collagen gene expression in L-tryptophan associated eosinophilia-myalgia syndrome skin fibroblasts. | J Rheumatol | To investigate the pathogenetic mechanisms responsible for the cutaneous fibrosis in eosinophilia-myalgia syndrome (EMS) associated with L-tryptophan ingestion.Compare in vitro type I collagen production and steady state procollagen mRNA levels in cultured skin fibroblasts derived from healthy individuals and from 5 patients with EMS and diffuse cutaneous induration.Cell lines derived from the affected skin from patients with EMS exhibited greater collagen production and higher steady state levels of alpha 1(I) procollagen mRNA compared with fibroblasts from age and sex matched healthy individuals. Exposure to interferon gamma reduced collagen synthesis in the EMS fibroblast lines. The rate of in vitro transcription of the COL1A1 gene was 30% higher in nuclei isolated from collagen overproducer EMS fibroblasts than in nuclei from normal fibroblasts.Fibroblasts derived from the involved skin of patients with EMS show increased expression of the alpha 1(I) procollagen gene in vitro compared to normal skin fibroblasts. The biosynthetically activated phenotype exhibited by EMS fibroblasts appears to be due, at least in part, to transcriptional activation of type I collagen gene expression. These biochemical and molecular alterations may result in accumulation of collagen and lead to the cutaneous fibrosis in EMS. |