Submission Details

Autosomal recessive

01/29/2019

The SPARC gene is located on chromosome 5 at 5q33.1 and encodes the secreted protein acidic and cysteine rich, or osteonectin protein. SPARC was first reported in relation to autosomal recessive osteogenesis imperfecta in 2015 (26027498: Mendoza-Londono et al. 2015). Evidence supporting this gene-disease relationship includes limited case-level data and experimental data. Two unique homozygous missense variants in this gene were reported in two unrelated patients who showed repeated fractures, kyphoscoliosis, joint hyperlaxity, and underdeveloped muscles of the lower extremities, resulting in a clinical diagnosis of osteogenesis imperfecta type IV (26027498: Mendoza-Londono et al. 2015). Both variants were located in the calcium binding domain responsible for the binding of SPARC to collagen, and skin fibroblasts from both patients showed collagen abnormalities suggestive of a damaging effect of the variants. Neither the heterozygous parents of the patients nor heterozygous mutant mice showed a phenotype. Loss of function has been suggested as the mechanism of disease, but additional evidence is needed. This gene-disease relationship is supported by expression data, protein-interaction data, and mouse model data. The SPARC protein is highly expressed in osseous tissue with high turnover (26851678: Rosset and Bradshaw 2016) and interacts with various forms of collagen (745554: Sage et al. 1989). Homozygous SPARC null mice develop low-turnover osteopenia, cataracts, intervertebral disc degeneration, and increased adiposity (9524110: Gilmour et al. 1998; 10749571: Delany et al. 2000; 12721366: Bradshaw et al. 2003; 15879573: Gruber et al. 2005). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship.

26027498 745554 26851678 10749571