ICCBH2015 Late Breaking Oral Communication Abstracts (1) (2 abstracts)
Recessive osteogenesis imperfecta caused by missense mutations in SPARC
Roberto Mendoza 1 , Somayyeh Fahiminiya 3 , Jacek Majewski 3 , Care4Rare Canada Consortium 1 , Martine Tétreault 3 , Javad Nadaf 3 , Peter Kannu 1 , Etienne Sochett 1 , Andrew Howard 1 , Jennifer Stimec 1 , Lucie Dupuis 1 , Paul Roschger 4 , Klaus Klaushofer 4 , Telma Palomo 2, , Jean Ouellet 2, , Hadil Al-Jallad 2 , John Mort 2, , Pierre Moffatt 2, , Sergei Boudko 2 , Hans-Peter Bachinger 5 & Frank Rauch 2,
1Hospital for Sick Children, Toronto, ON, Canada; 2Shriners Hospital, Montreal, QC, Canada; 3McGill University, Montreal, QC, Canada; 4Ludwig Boltzmann Institute of Osteology, Vienna, Austria; 5Shriners Hospital, Portland, OR, USA.
Objectives: We sought to identify the disease-causing mutations in two unrelated girls with a clinical diagnosis of osteogenesis imperfecta type IV.
Methods: Whole-exome sequencing and cellular studies in skin fibroblasts were conducted.
Results: We identified two homozygous variants in SPARC (NM_003118.3; c.497G>A (p.Arg166His) in individual 1; c.787G>A (p.Glu263Lys) in individual 2). Secreted protein, acidic, cysteine-rich (SPARC) is a glycoprotein that binds to collagen type I and other proteins in the extracellular matrix. 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.
Conclusion: In conclusion, these observations show that homozygous mutations in SPARC can give rise to severe bone fragility in humans.
Disclosure: The authors declared no competing interests.
Volume 4
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