Clcn7^F318L/+ as a new mouse model of Albers-Schönberg disease.

Abstract

Dominant negative mutations in CLCN7, which encodes a homodimeric chloride channel needed for matrix acidification by osteoclasts, cause Albers-Schönberg disease (also known as autosomal dominant osteopetrosis type 2). More than 25 different CLCN7 mutations have been identified in patients affected with Albers-Schönberg disease, but only one mutation (Clcn7^G213R) has been introduced in mice to create an animal model of this disease. Here we describe a mouse with a different osteopetrosis-causing mutation (Clcn7^F318L). Compared to Clcn7^+/+ mice, 12-week-old Clcn7^F318L/+ mice have significantly increased trabecular bone volume, consistent with Clcn7^F318L acting as a dominant negative mutation. Clcn7^F318L/F318L and Clcn7^F318L/G213R mice die by 1month of age and resemble Clcn7 knockout mice, which indicate that p.F318L mutant protein is non-functional and p.F318L and p.G213R mutant proteins do not complement one another. Since it has been reported that treatment with interferon gamma (IFN-G) improves bone properties in Clcn7^G213R/+ mice, we treated Clcn7^F318L/+ mice with IFN-G and observed a decrease in osteoclast number and mineral apposition rate, but no overall improvement in bone properties. Our results suggest that the benefits of IFN-G therapy in patients with Albers-Schönberg disease may be mutation-specific.