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Case Reports
, 26 (12), 2798-803

Mutations in SERPINF1 Cause Osteogenesis Imperfecta Type VI

Case Reports

Mutations in SERPINF1 Cause Osteogenesis Imperfecta Type VI

Erica P Homan et al. J Bone Miner Res.


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 (SERPINF1) 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.


Fig 1
Fig 1
(A) The pedigree of the French Canadian index family. The great-grandfather of patient V-1 and the grandfather of patients IV-3 and IV-4 are brothers. In addition, subjects III-3 and IV-2 are also related (not shown). (B) There were no signs of rickets in patient V-1 at the age of 25 months even though bone histology showed impaired mineralization of bone tissue at the same time. The sclerotic area below the radial growth plate is a typical sign of pamidronate treatment. Lower extremity radiographs of patient V-1 at the ages of (C) 9 months and (D) 8 years, and (E) of patient IV-3 at the age of 21 years, showing the evolution of OI type VI from bones with normal appearance in the first year of life to bulbous ‘popcorn’ epiphyses (arrows) and thin diaphysis later. (C) A fracture crack was present in the proximal femur; however, it is too faint to be visible in the reproduced figure. (F-I) Iliac bone histology (F and G) in an age-matched control and (H and I) in patient IV-3 at 13 years of age. The left panels (F and H) show Goldner-stained sections and show a large quantity of unmineralized osteoid (red color) (H) in the trabecular bone of patient IV-3, indicative of a mineralization defect. The right panels (G and I) represent toluidine blue-stained sections of the same samples seen under polarized light, showing smooth bone lamellation (G, inset box) in the control and ‘fish-scale’ pattern (I, inset box) in patient IV-3. The quantitative histomorphometric results in patient IV-3, including dynamic measures based on tetracycline labeling, had been included in an earlier report. The size bars represent 100µm.
Fig 2
Fig 2
(A) Sanger sequencing confirmation of g.4130C>T, p.R99X in patient IV-3 as compared with control and parent (III-3, III-4). (B) Sanger sequencing confirmation of g.10440_10443dupATCA, p.H389f3sX392 in the Italian boy as compared with control and parent. (C) Quantitative RT-PCR of SERPINF1 in patient fibroblasts shows dramatically decreased levels of SERPINF1 transcript in patients V-I and IV-3 (g.4130C>T, p.R99X) as compared with control fibroblasts, suggesting nonsense-mediated decay of the transcript. (D) PEDF serum levels in all three OI type VI patients are below the detectable limits of the assay (0.03ng/mL) as compared with classical OI controls.

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