Recessive Osteogenesis Imperfecta Caused by Missense Mutations in SPARC

Abstract

Secreted protein, acidic, cysteine-rich (SPARC) is a glycoprotein that binds to collagen type I and other proteins in the extracellular matrix. Using whole-exome sequencing to identify the molecular defect in two unrelated girls with severe bone fragility and a clinical diagnosis of osteogenesis imperfecta type IV, we identified two homozygous variants in SPARC (GenBank: NM_003118.3; c.497G>A [p.Arg166His] in individual 1; c.787G>A [p.Glu263Lys] in individual 2). Published modeling and site-directed mutagenesis studies had previously shown that the residues substituted by these mutations form an intramolecular salt bridge in SPARC and are essential for the binding of SPARC to collagen type I. The amount of SPARC secreted by skin fibroblasts was reduced in individual 1 but appeared normal in individual 2. The migration of collagen type I alpha chains produced by these fibroblasts was mildly delayed on SDS-PAGE gel, suggesting some overmodification of collagen during triple helical formation. Pulse-chase experiments showed that collagen type I secretion was mildly delayed in skin fibroblasts from both individuals. Analysis of an iliac bone sample from individual 2 showed that trabecular bone was hypermineralized on the material level. In conclusion, these observations show that homozygous mutations in SPARC can give rise to severe bone fragility in humans.

What every clinical geneticist should know about testing for osteogenesis imperfecta in suspected child abuse cases

“…If a causative variant is not identified, in the absence of a significant pathologic clinical phenotype, no additional gene testing is indicated. Sixteen (16) genes are presently known to play a role in fracture susceptibility in children with recessively inherited forms of OI [Byers and Pyott, 2012;Cho et al, 2012;Lapunzina et al, 2010;Mart ınez-Glez et al, 2012;Semler et al, 2012;Shaheen et al, 2012;Pyott et al, 2013;Symoens et al, 2013;Garbes et al, 2015;Mendoza-Londono et al, 2015;Rauch et al, 2015]. In total, these account for less than 10% of all individuals identified with OI.…”

Bone Material Properties in Osteogenesis Imperfecta

“…Cartilage associated protein Yes Severe-lethal OI; (114,115) Cole-Carpenter features (116) Collagen (121) Collagen processing/cleavage BMP1 Bone morphogenetic protein 1; tolloid Yes High bone mass, hyperosteoidosis (122) Osteoblast lineage/function Wnt-signaling pathway LRP5/6…”

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

“…Thirteen genes have already been described to be targets of autosomal recessive mutations in OI: LEPRE1 (Cabral et al, 2007), CRTAP (Morello et al, 2006), PPIB (van Dijk et al, 2009), FKBP10 (Alanay et al, 2010), SERPINH1 (Christiansen et al, 2010), SERPINF1 (Becker et al, 2011), PLOD2 (Puig-Hervás et al, 2012, TMEM38B (Shaheen et al, 2012), BMP1 (Martínez-Glez et al, 2012), WNT1 (Fahiminiya et al, 2013), SP7 (Lapunzina et al, 2010), CREB3L1 (Symoens et al, 2013), and SPARC (Mendoza-Londono et al, 2015).…”