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Recessive osteogenesis imperfecta caused by missense mutations in SPARC.

Mendoza-Londono R, Fahiminiya S, Majewski J, Care4Rare Canada Consortium, Tétreault M, Nadaf J, Kannu P, Sochett E, Howard A, Stimec J, Dupuis L, Roschger P, Klaushofer K, Palomo T, Ouellet J, Al-Jallad H, Mort JS, Moffatt P, Boudko S, Bächinger HP, Rauch F
Am J Hum Genet. 2015 96 (6): 979-85

PMID: 26027498 · PMCID: PMC4457955 · DOI:10.1016/j.ajhg.2015.04.021

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.

Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

MeSH Terms (19)

Amino Acid Sequence Base Sequence Collagen Type I Electrophoresis, Polyacrylamide Gel Exome Female Genes, Recessive Humans Immunoblotting Models, Molecular Molecular Sequence Data Mutagenesis, Site-Directed Mutation, Missense Osteogenesis Imperfecta Osteonectin Pedigree Protein Conformation Sequence Alignment Sequence Analysis, DNA

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