C1cn7F318L/+ as a new mouse model of Albers-Schonberg disease

Dominant negative mutations in CLCN7, which encodes a homodimeric chloride channel needed for matrix acidification by osteoclasts, cause Albers-Schonberg disease (also known as autosomal dominant osteopetrosis type 2). More than 25 different CLCN7 mutations have been identified in patients affected with Albers-SchOnberg 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 ciai7(F318L/G213R) mice die by 1 month 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-Schonberg disease may be mutation-specific. (C) 2017 Elsevier Inc. All rights reserved.