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Secreted protein acidic and rich in cysteine (SPARC) has been implicated in autosomal recessive osteogenesis imperfecta type IV, a moderate-to-severe bone fragility disorder. SPARC binds collagen I in the extracellular matrix, stabilizing fibril formation and mineralization. Disruption of SPARC impairs collagen secretion and bone matrix homeostasis, consistent with observed patient phenotypes.
Genetic evidence arises from whole-exome sequencing in two unrelated girls with clinical osteogenesis imperfecta type IV, each harboring homozygous missense variants in SPARC (c.497G>A (p.Arg166His), c.787G>A (p.Glu263Lys)) (PMID:26027498). These findings indicate autosomal recessive inheritance with 2 probands and 2 unrelated families; no additional affected relatives were reported (PMID:26027498). Both variants affect residues forming an intramolecular salt bridge crucial for collagen binding.
Functional assays on patient skin fibroblasts demonstrated reduced SPARC secretion in one individual and normal secretion in the other, yet both showed a mild delay in collagen I secretion and overmodification of collagen fibrils during triple helix formation. Pulse-chase experiments confirmed delayed collagen export, and iliac bone analysis revealed trabecular hypermineralization (PMID:26027498). These data support a hypomorphic mechanism of pathogenicity, where partial SPARC function leads to defective extracellular matrix assembly.
Previously published modeling and site-directed mutagenesis established that Arg166 and Glu263 participate in SPARC–collagen salt bridges essential for matrix interaction; disruption of these contacts corroborates the patient fibroblast phenotypes. The concordance between molecular modeling, in vitro secretion defects, and in vivo bone mineralization abnormalities fulfills moderate experimental evidence for disease causality.
No conflicting reports have been described for SPARC variants in osteogenesis imperfecta type IV, and the specificity of the collagen secretion phenotype strongly supports disease association. Further studies of carrier frequency and extended segregation would solidify the genotype–phenotype correlation.
Key Take-home: SPARC should be included in genetic testing panels for autosomal recessive osteogenesis imperfecta type IV to enable precise molecular diagnosis and inform clinical management.
Gene–Disease AssociationModerate2 unrelated homozygous probands with concordant functional data Genetic EvidenceLimitedTwo homozygous cases in unrelated families; no segregation beyond probands Functional EvidenceModerateIn vitro fibroblast assays and bone analyses demonstrate secretion defects and matrix mineralization abnormalities |