ORPHA: 216812, 216820, 666; DO: 0110350;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 17p13.3 | Osteogenesis imperfecta, type VI | 613982 | Autosomal recessive | 3 | SERPINF1 | 172860 |
A number sign (#) is used with this entry because of evidence that osteogenesis imperfecta type VI (OI6) is caused by homozygous mutation in the SERPINF1 gene (172860) on chromosome 17p13.3.
Osteogenesis imperfecta (OI) comprises a group of connective tissue disorders characterized by bone fragility and low bone mass. The disorder is clinically and genetically heterogeneous. Osteogenesis imperfecta type VI is a severe autosomal recessive form of the disorder (Glorieux et al., 2002; Becker et al., 2011).
Glorieux et al. (2002) described a novel form of OI, which they designated OI type VI, in 8 patients (6 males). None of the patients, all of whom had earlier been diagnosed with OI type IV (166220) (Ward et al., 2000), had documented fractures at birth. Fractures were first documented between ages 4 and 18 months. Type VI OI patients sustained more frequent fractures than patients with OI type IV, which led to long bone deformity in 7 of the patients. Ligamentous laxity was present in 4 of the patients. Sclerae were white or faintly blue and teeth were normal. Radiologic findings included long bone deformity, coxa vara, and protrusio acetabuli. The vertebrae were wedge-shaped or biconcave. All patients had vertebral compression fractures. Wormian bones of the skull were absent. Lumbar spine bone mineral density (aBMD) was low and similar to age-matched patients with OI type IV. Two brothers, born to consanguineous parents, were unusual in that they showed severe osteopenia, bulbous metaphyses, and severe limb deformity. Histology of iliac biopsy specimens revealed a distinctive 'fish-scale' pattern of the lamellae. Another distinctive feature was the presence of excessive osteoid. Glorieux et al. (2002) concluded that the hyperosteoidosis points toward a defect in mineralization. Levels of biochemical bone markers were generally within the reference range but serum alkaline phosphatase levels were elevated compared to the levels in patients with OI type IV.
Becker et al. (2011) described 4 affected individuals from 3 unrelated consanguineous families with a severe form of OI, which the authors stated was compatible with OI type III in the Sillence classification (see 259420). No intrauterine fractures were reported, and birth length and weight were normal. Dentinogenesis imperfecta was not present, and the sclerae were grayish. All 4 individuals had fractures of long bones and severe vertebral compression fractures, with resulting deformities observed as early as the first year of life. Bone mineral density was severely reduced. All had short stature and were wheelchair bound.
Land et al. (2007) described the results of 3 years of pamidronate treatment in 10 children and adolescents with OI type VI (age range 0.8 to 14.5 years). Treatment effects were compared to those of 10 patients with OI types I, III, and IV, who were matched for age and disease severity. During pamidronate therapy, lumbar spine areal bone mineral density z scores increased and lumbar spine vertebral bodies improved in shape. Iliac bone histomorphometry showed a tendency to higher cortical thickness (+53%, p = 0.06), but the mineralization defect, a characteristic feature of OI type VI, did not change during pamidronate treatment. Annualized fracture incidence decreased from 3.1 per year before treatment to 1.4 fractures per year during treatment (p less than 0.05).
From their study, Glorieux et al. (2002) could not ascertain the mode of inheritance of OI type VI. The 3 boys (including 2 brothers) with the most severe phenotype were products of consanguineous parents, suggesting recessive inheritance. However, Glorieux et al. (2002) noted that for the 2 brothers, parental mosaicism with autosomal dominant inheritance was possible.
Becker et al. (2011) confirmed autosomal recessive inheritance of OI type VI.
Becker et al. (2011) applied next-generation sequencing and identification of homozygous regions to analyze the exome of a single male individual, the offspring of consanguineous parents, who had a severe form of OI. They identified a homozygous truncating mutation in the SERPINF1 gene (172860.0001), which was also found in his affected brother. Their parents and 2 unaffected sisters were heterozygous carriers. Becker et al. (2011) also identified homozygosity for different truncating SERPINF1 mutations in 2 unrelated Turkish patients with severe OI (172860.0002-172860.0003). Collagen analyses with cultured dermal fibroblasts displayed no evidence for impaired collagen folding, posttranslational modification, or secretion.
In affected members of 3 Saudi families with OI, Shaheen et al. (2012) identified homozygous mutations in the SERPINF1 gene (172860.0004-172860.0006). All of those affected had early childhood onset of fractures, and affected individuals in 2 families had blue sclera. There was no apparent involvement of the teeth or other organs. All responded well to bisphosphonate therapy.
PEDF Interaction with BRIL
Farber et al. (2014) found that a missense mutation in the IFITM5 gene (S40L; 614757.0002) that resulted in OI (OI5; 610967) affected expression and secretion of PEDF. While IFITM5 expression was normal in proband fibroblasts and osteoblasts, and BRIL protein (the product of the IFITM5 gene) level was similar to controls, secretion of PEDF by patient fibroblasts was barely detectable, and analysis of patient osteoblasts confirmed minimal secretion of PEDF. The patient's phenotypic and bone histologic findings were most consistent with OI type VI. Farber et al. (2014) concluded that BRIL and PEDF have a relationship that connects the genes for OI types V and VI and their roles in bone mineralization.
Exclusion Studies
Glorieux et al. (2002) screened both type I collagen genes (COL1A1 and COL1A2) using cDNA and genomic DNA and detected no mutations in their patients.
The form of OI caused by mutation in the SERPINF1 gene was originally designated OI type XII (OI12) in OMIM.
Becker, J., Semler, O., Gilissen, C., Li, Y., Bolz, H. J., Giunta, C., Bergmann, C., Rohrbach, M., Koerber, F., Zimmermann, K., de Vries, P., Wirth, B., Schoenau, E., Wollnik, B., Veltman, J. A., Hoischen, A., Netzer, C. Exome sequencing identifies truncating mutations in human SERPINF1 in autosomal-recessive osteogenesis imperfecta. Am. J. Hum. Genet. 88: 362-371, 2011. [PubMed: 21353196] [Full Text: https://doi.org/10.1016/j.ajhg.2011.01.015]
Farber, C. R., Reich, A., Barnes, A. M., Becerra, P., Rauch, F., Cabral, W. A., Bae, A., Quinlan, A., Glorieux, F. H., Clemens, T. L., Marini, J. C. A novel IFITM5 mutation in severe atypical osteogenesis imperfecta type VI impairs osteoblast production of pigment epithelium-derived factor. J. Bone Miner. Res. 29: 1402-1411, 2014. [PubMed: 24519609] [Full Text: https://doi.org/10.1002/jbmr.2173]
Glorieux, F. H., Ward, L. M., Rauch, F., Lalic L., Roughley, P. J., Travers, R. Osteogenesis imperfecta type VI: a form of brittle bone disease with a mineralization defect. J. Bone Miner. Res. 17: 30-38, 2002. [PubMed: 11771667] [Full Text: https://doi.org/10.1359/jbmr.2002.17.1.30]
Land, C., Rauch, F., Travers, R., Glorieux, F. H. Osteogenesis imperfecta type VI in childhood and adolescence: effects of cyclical intravenous pamidronate treatment. Bone 40: 638-644, 2007. [PubMed: 17127117] [Full Text: https://doi.org/10.1016/j.bone.2006.10.010]
Shaheen, R., Alazami, A. M., Alshammari, M. J., Faqeih, E., Alhashmi, N., Mousa, N., Alsinani, A., Ansari, S., Alzahrani, F., Al-Owain, M., Alzayed, Z. S., Alkuraya, F. S. Study of autosomal recessive osteogenesis imperfecta in Arabia reveals a novel locus defined by TMEM38B mutation. J. Med. Genet. 49: 630-635, 2012. [PubMed: 23054245] [Full Text: https://doi.org/10.1136/jmedgenet-2012-101142]
Ward, L. M., Lalic, L., Lalic, R., Roughley, P., Rauch, F., Plotkin, H., Travers, R., Glorieux, F. H. The clinical, molecular and histological heterogeneity of type IV osteogenesis imperfecta. (Abstract) J. Bone Miner. Res. 15: S163 only, 2000.