Refined Genomic Localization of the Genetic Lesion in the Osteopetrosis (op) Rat and Exclusion of Three Positional and Functional Candidate Genes, Clcn7, Atp6v0c, and Slc9a3r2

Abstract

Osteopetrosis is a disease characterised by a generalized skeletal sclerosis resulting from a reduced osteoclast-mediated bone resorption. Several spontaneous mutations lead to osteopetrotic phenotypes in animals. Moutier et al. (1974) discovered the osteopetrosis (op) rat as a spontaneous, lethal, autosomal recessive mutant. op rats have large non-functioning osteoclasts and severe osteopetrosis [1]. Dobbins et al. (2002) localised the disease causing gene to a 1.5 cM genetic interval on rat chromosome 10, which we confirm in the present report [2]. We also refined the genomic localisation of the disease gene and provide statistical evidence for a disease causing gene in a small region of rat chromosome 10. Three strong functional candidate genes are within the delineated region. Clcn7 was previously shown to underlie different forms of osteopetrosis, both in human and mice. ATP6v0c encodes a subunit of the vacuolar H(+)-ATPase or proton-pump. Mutations in TCIRG1, another subunit of the proton-pump, are known to cause a severe form of osteopetrosis. Given the critical role of proton pumping in bone resorption, the Slc9a3r2 gene, a sodium/hydrogen exchanger, was also considered as a candidate for the op mutation. RT-PCR showed that all 3 genes are expressed in osteoclasts, but sequencing found no mutations in either the coding regions nor in intron splice junctions. Our ongoing mutation analysis of other genes in the candidate region will lead to the discovery of a novel osteopetrosis gene and further insights into osteoclast functioning.

The cast of clasts: catabolism and vascular invasion during bone growth, repair, and disease by osteoclasts, chondroclasts, and septoclasts

“…Septoclasts remained fewer in number and disorganized despite CSF-1 injections (60). Another rat model, osteopetrosis ( op – n.b ., not to be confused with the op mouse, which is CSF-1 deficient and osteoclast-poor) is a recessive allele at an unknown locus on chromosome 10 (72, 73) which causes bone disease very similar in severity to that seen in the tl rat (74); however the op/op rat has abundant, but non-functioning osteoclasts (osteoclast-rich osteopetrosis), and its growth plates are not abnormally thickened over time (8). …”

Report of two Chinese patients suffering from CLCN7-related osteopetrosis and root dysplasia

“…Osteopetrosis is a heterogeneous group of genetic bone disorders caused by failure of osteoclast generation or function (Besbas et al, 2009;Furthner et al, 2010;Kajiya et al, 2009;Perdu et al, 2009;Phadke et al, 2010). Based on its severity and secondary clinical features, age of onset and means of inheritance, osteopetrosis is classified into three types: autosomal recessive osteopetrosis (ARO), autosomal dominant osteopetrosis type II (ADO II), and intermediate autosomal recessive osteopetrosis (IARO) (Besbas et al, 2009;Pangrazio et al, 2009;Perdu et al, 2009).…”

“…Based on its severity and secondary clinical features, age of onset and means of inheritance, osteopetrosis is classified into three types: autosomal recessive osteopetrosis (ARO), autosomal dominant osteopetrosis type II (ADO II), and intermediate autosomal recessive osteopetrosis (IARO) (Besbas et al, 2009;Pangrazio et al, 2009;Perdu et al, 2009). So far, mutations in at least 10 different genes (TCIRG1, CLCN7, PLEKHM1, OSTM1, CA2, RANK, RANKL and so on) have been identified as candidate genes in different types of osteopetrosis in human (Campos-Xavier et al, 2003).…”