Identification of two novel mutations on CLCN7 gene in a patient with malignant ostopetrosis

BACKGROUND: Osteopetrosis is a rare genetic disorder characterized by increased bone density due to a defective osteoclast’s bone resorption. Three clinical forms can be identified based on severity, age of onset and inheritance: the dominant benign form (ADO), the intermediate form (IRO) and the recessive severe form (ARO). Several genes have been involved in the pathogenesis of these different types of osteopetrosis. Many experimental evidences point out on a specific role for CLCN7, the gene encoding the chloride channel protein subunit alfa and for TCIRG1, the gene encoding an osteoclast specific subunit of the vacuolar proton pump. Mutations in CLCN7 gene have been associated to the complete spectrum of osteopetrosis ranging from ARO to IRO and even to ADO type II. On the other hand, mutations in TCIRG1 gene account for more than 50% of cases of ARO. It is then evident that the malignant osteopetrosis is characterized by a great molecular and clinical heterogeneity often making the final diagnosis difficult to achieve. METHODS: We performed a complete clinical, biochemical and molecular analysis by PCR and direct sequencing, of a novel case of osteopetrosis with inconsistent clinical phenotype. RESULTS: The patient, who cannot be ascribed to any of the ADO, ARO or IRO groups, carried two novel mutations in compound heterozygosis in the CLCN7 gene. The first was the missense mutation c. 948C > T on exon 10 that produces an Arg to Cys change, while the second was the IVS11 + 5G > A splicing mutation that resides on the donor splice site of intron 11 and distrupts the canonical splice site. CONCLUSION: Our data: a. Demonstrate that the unusual clinical presentation observed in our patient with a mild clinical onset evolving towards a more serious clinical picture, is associated to two novel mutations on CLCN7 gene. b. Support the already described clinical and molecular heterogeneity of the malignant osteopetrosis. c. Suggest that, performing a molecular diagnosis of osteopetrosis with inconsistent clinical presentation these two novel mutations have to be first considered.