Mutations in SERPINF1 cause osteogenesis imperfecta type VI

Abstract

Osteogenesis imperfecta (OI) is a spectrum of genetic disorders characterized by bone fragility. It is caused by dominant mutations affecting the synthesis and/or structure of type I procollagen or by recessively inherited mutations in genes responsible for the posttranslational processing/trafficking of type I procollagen. Recessive OI type VI is unique among OI types in that it is characterized by an increased amount of unmineralized osteoid, thereby suggesting a distinct disease mechanism. In a large consanguineous family with OI type VI, we performed homozygosity mapping and next-generation sequencing of the candidate gene region to isolate and identify the causative gene. We describe loss of function mutations in serpin peptidase inhibitor, clade F, member 1 (SERPINF 1) in two affected members of this family and in an additional unrelated patient with OI type VI. SERPINF1 encodes pigment epithelium-derived factor. Hence, loss of pigment epithelium-derived factor function constitutes a novel mechanism for OI and shows its involvement in bone mineralization. © 2011 American Society for Bone and Mineral Research

Osteogenesis Imperfecta

“…Recently mutations in SERPINF1, encoding the pigment epithelium derived factor (PEDF) have been identified in a few cases of recessive OI some of which were originally classified as OI type VI (Becker et al, 2011;Glorieux et al, 2002;Homan et al, 2011). Clinically these patients are born of normal weight and length, without fractures, limb deformities or joint laxity, with gray-white sclerae and normal facial features.…”

“…They can begin to fracture early (before the first year of life) and progress to experience several other fractures which result in bone deformities and usually lack or loss of ambulation. The progressive worsening of the symptoms suggests a post-natal early onset of the skeletal phenotype; importantly, at the histological level, iliac bone biopsies show a large amount of un-mineralized osteoid on their cancellous bone due to a mineralization defect and a 'fish-scale' pattern of bone deposition instead of normal bone lamellation Homan et al, 2011). All patients identified were homozygous for either nonsense mutations or frameshift mutations leading to a premature termination codon and likely to nonsense-mediated RNA decay, resulting in null alleles.…”

Genetic epidemiology, prevalence, and genotype–phenotype correlations in the Swedish population with osteogenesis imperfecta

“…[1][2][3][4][5][6][7][8][9][10][11][12][13] On the contrary, here 15/32 families with no mutation in collagen I had a typical type I phenotype, and 25 additional families were excluded on the basis of a negative sequencing result in combination with an unclear clinical phenotype. These individuals may have a COL1A1 null allele caused by a non-exonic mutation missed here; however, another OI-related gene might be causative in some instances.…”

“…Dominant mutations in collagen type I are generally stated to be responsible for 90% of cases, while a plethora of other genes have been associated with non-collagen OI in recent years. [1][2][3][4][5][6][7][8][9][10][11][12][13] Collagen type I, encoded by COL1A1 and COL1A2, constitutes 85% of the organic matrix in skeletal tissue, and forms a framework for mineral deposition, rendering bone the tensile properties needed to withstand torsion and bending powers. Procollagen is a heterotrimer, with a helical 1014-amino acid-long central stretch of two α1-and one α2-chains, which is flanked by globular N-and C-terminal regions.…”

Osteogenesis imperfecta

“…Osteogenesis imperfecta type VI is caused by reces sive null mutations in SERPINF1, which encodes pigment epithelium derived factor (PEDF). PEDF is an anti angiogenic factor that also interacts with recep tor activator of nuclear factor κβ ligand (RANKL; also known as TNFSF11) pathway, thereby increasing the activity of osteoclasts [83][84][85] (FIG. 4a).…”