2. Academic Validation
  3. Recessive osteogenesis imperfecta caused by missense mutations in SPARC

Recessive osteogenesis imperfecta caused by missense mutations in SPARC

  • Am J Hum Genet. 2015 Jun 4;96(6):979-85. doi: 10.1016/j.ajhg.2015.04.021.
Roberto Mendoza-Londono 1,  Somayyeh Fahiminiya 2,  Jacek Majewski 2,  Care4Rare Canada Consortium,  Martine Tétreault 2,  Javad Nadaf 2,  Peter Kannu 1,  Etienne Sochett 3,  Andrew Howard 4,  Jennifer Stimec 5,  Lucie Dupuis 1,  Paul Roschger 6,  Klaus Klaushofer 6,  Telma Palomo 7,  Jean Ouellet 7,  Hadil Al-Jallad 7,  John S Mort 7,  Pierre Moffatt 7,  Sergei Boudko 8,  Hans-Peter Bächinger 8,  Frank Rauch 9
Affiliations

Affiliations

  • 1 Department of Paediatrics, Division of Clinical and Metabolic Genetics, The Hospital for Sick Children and University of Toronto, Toronto, ON M5G 1X8, Canada; The Bone Health Centre, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
  • 2 Department of Human Genetics, McGill University and Génome Québec Innovation Centre, Montréal, QC H3A 1B1, Canada.
  • 3 The Bone Health Centre, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Division of Endocrinology, Department of Paediatrics, The Hospital for Sick Children and University of Toronto, Toronto, ON M5G 1X8, Canada.
  • 4 The Bone Health Centre, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Orthopaedic Surgery, The Hospital for Sick Children and The University of Toronto, Toronto, ON M5G 1X8, Canada.
  • 5 The Bone Health Centre, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Diagnostic Imaging, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
  • 6 Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of WGKK and AUVA Trauma Center Meidling, 1st Med. Department, Hanusch Hospital, Vienna 1140, Austria.
  • 7 Shriners Hospital for Children, Montréal, QC H3G 1A6, Canada.
  • 8 Shriners Hospital for Children, Portland, OR 97239, USA.
  • 9 Shriners Hospital for Children, Montréal, QC H3G 1A6, Canada. Electronic address: frauch@shriners.mcgill.ca.
PMID: 26027498 DOI: 10.1016/j.ajhg.2015.04.021
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.

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