Identification of rank mutations in patients with osteoclast-poor autosomal recessive osteopetrosis

Autosomal recessive osteopetrosis (ARO) is a rare bone disease characterized by increased bone density, fractures, bone marrow fibrosis and secondary pancytopenia and hepatolosplenomegaly. Neurological disorders can occur due to nerve entrapment or as primary defect. Our group has contributed to the dissection of the molecular basis of this complex and heterogeneous disorder, demonstrating that mutations in TCIRG1 are the main cause of ARO, explaining about 60% of patients (Frattini et al, 2000). Mutations in ClCN7 and in OSTM1 account for an additional 15% of cases of ARO characterized by normal or higher number of osteoclasts (osteoclast-rich ARO). Of note, these two latter forms are associated with primary neural defects. Recently, our group has identified a new subset of patients affected by ARO whose bone biopsies show no osteoclasts (osteoclast-poor ARO) carrying mutations in RANKL gene (Sobacchi et al, 2007) who do not benefit from bone marrow transplantation (BMT). Thus the identification of this clinical subset of patients is important to explore new therapeutic strategies. In the present work, we have further investigated the molecular basis of osteoclast- poor ARO. In particular, we have analyzed the RANKL-RANK pathway in patients whose biopsies do not show osteoclasts and without mutations in the RANKL gene. We identified six novel mutations in the RANK gene in 5 unrelated families. Our findings add further complexity to the heterogeneous field of ARO and demonstrate that a careful molecular diagnosis can be important not only to understand the biology of the disease, but also to choose the clinical strategy.