Lack of expression of SERPINF1, the gene coding for pigment epithelium-derived factor, causes progressively deforming osteogenesis imperfecta with normal type I collagen

Abstract

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

Novel Deletion of <b><i>SERPINF1</i></b> Causes Autosomal Recessive Osteogenesis Imperfecta Type VI in Two Brazilian Families

“…Radiological findings are non-distinctive in this type of OI and include bowing of long bones, vertebral compression fractures, generalized osteopenia, hyperplastic callus formation, and absence of wormian bones in the majority of cases [Becker et al, 2011]. Patients with OI type VI apparently do not respond to bisphosphonate treatment as well as patients with other types of OI [Venturi et al, 2012b].…”

“…BMP1 (MIM 112264) is involved in the C-terminal processing of procollagen chains [Asharani et al, 2012]. SERPINF1 (MIM 172860) encodes pigment epithelium-derived factor (PEDF), a secreted glycoprotein with high affinity to collagens of the extracellular matrix, and it is speculated that a loss of PEDF causes OI independent of collagen type I biosynthesis [Becker et al, 2011;Rauch et al, 2012;Venturi et al, 2012b]. TMEM38B (MIM 611236) encodes TRIC-B (trimeric intracellular cation channel type b), a ubiquitous component of TRIC, a monovalent cation-specific channel involved in Ca 2+ release from intracellular stores that has been shown to act in cell differentiation.…”

Proteomic Analysis of Gingival Tissue and Alveolar Bone during Alveolar Bone Healing

“…SERPINF1 expression changes with the progression of various tumor types (39), which suggests that SERPINF1 may direct cellular fate. It was also recently reported that a frameshift mutation in exon 4 of the SERPINF1 gene that reduced expression of the transcription/translation product and causes progressively deforming osteogenesis imperfecta is likely a key factor in bone deposition and remodeling (40).…”

Analysis of FKBP10, SERPINH1, and SERPINF1 genes in patients with osteogenesis imperfecta

“…PEDF is a strong inhibitor of angiogenesis, and works by suppressing endothelial cell migration and proliferation and induction of endothelial cell apoptosis (Quan et al, 2005). PEDF has a high affinity for the collagens that form the extracellular matrix (Venturi et al, 2012b). In bones, it regulates osteoprotegerin, which inhibits the maturation of osteoclasts, blocking proliferation and differentiation of the precursors of these cells.…”