Autosomal recessive osteopetrosis: report of 41 novel mutations in the TCIRG1 gene and diagnostic implications

Summary Here we report 41 novel mutations in the TCIRG1 gene that is responsible for the disease in more than 50% of ARO patients. The characterisation of mutations in this gene might be useful in the process of drug design for osteoporosis treatment. Introduction Autosomal recessive osteopetrosis (ARO) is a genetically heterogeneous disorder due to reduced bone resorption by osteoclasts. In this process, a crucial role is played by the proton pump V-ATPase. Biallelic mutations in the TCIRG1 gene, encoding for the a3 subunit of this pump, are responsible for more than one half of ARO patients. Methods Patients with a clinical diagnosis of ARO have been collected for 7 years and mutation analysis of the TCIRG1 gene was performed using direct DNA sequencing of PCR-amplified exons according to both a standard protocol and a modified one. Results We report here 41 novel mutations identified in 67 unpublished patients, all with biallelic mutations. In particular, we describe two novel large genomic deletions and two splice site mutations in the 5′ UTR of the TCIRG1 gene, in patients previously classified as mono-allelic. Conclusions Our data highlights the importance of two large genomic deletions and mutations in the 5′ UTR with respect to patient management and, more critically, to prenatal diagnosis. With the present work, we strongly contribute to the molecular dissection of TCIRG1-deficient ARO and identify several protein residues which are fundamental for proton pump function and could thus be the target of future drugs designed to inhibit osteoclast resorptive activity.