Identification of a novel mutation in the coding region of the grey-lethal geneOSTM1in human malignant infantile osteopetrosis

Abstract

Autosomal recessive malignant infantile osteopetrosis (ARO) is characterized by severe osteosclerosis, pathologic fractures, hepatosplenomegaly, and pancytopenia. The pathophysiological basis is inadequate bone resorption due to osteoclast dysfunction. In the majority of cases, mutations in either of two human genes cause this fatal disorder: TCIRG1, encoding a subunit of the osteoclast H(+)-ATPase, and the voltage-gated chloride channel gene CLCN7. We excluded both genes in a small inbred family with malignant infantile osteopetrosis and undertook linkage analysis of several candidate loci that are involved in murine osteopetrosis. A region spanning more than 20 cM between the markers D6S1717 and D6S1608 on chromosome 6q21 was found to be homozygous in the affected child. This locus is syntenic to the genomic region harboring the gene for the osteopetrotic mutant mouse grey-lethal (gl). Recently, mutations in a novel gene of unknown function were described in the grey-lethal mouse and in one human patient. Mutation screening of the grey-lethal gene (OSTM1), revealed a homozygous 2-bp deletion in exon 2 (c.415_416delAG) in the affected child. No mutations could be found in six independent ARO patients who had tested negative for mutations in TCIRG1 and CLCN7. In summary, we describe the identification of a novel mutation in the coding sequence of the human grey-lethal gene, which is the second OSTM1 mutation found in human ARO, confirming the involvement of this gene in the pathogenesis of this severe bone disease.

Involvement of PLEKHM1 in osteoclastic vesicular transport and osteopetrosis in incisors absent rats and humans

“…The α 3 subunit of the H + ATPase, encoded by the TCIRG1 gene, is involved in the transportation of these protons through the ruffled border into the resorption lacuna (3,4), while chloride channel 7 (CLC7), encoded by the CLCN7 gene, translocates chloride ions to maintain electroneutrality (5)(6)(7). Finally, the OSTM1 gene encodes a type I transmembrane protein with E3 ubiquitin ligase activity (8)(9)(10)(11). The exact function of Ostm1 remains elusive, but a recent report identified the Ostm1 protein as a β subunit of CLC7 and demonstrated that it requires CLC7 to localize to lysosomes (12).…”

OSTM1 regulates β-catenin/Lef1 interaction and is required for Wnt/β-catenin signaling

“…Severe autosomal recessive osteopetrosis is a genetic disorder caused by mutations in several genes affecting osteoclast function, leading to fragile bones and increased infection rates [16,17]. Recently, defects in the OSTM1 gene have been found to generate ARO, both in humans and in the spontaneous grey-lethal mouse model.…”

“…Patients with autosomal recessive osteopetrosis suffer from frequent fractures, hepatosplenomegaly and bone marrow obliteration, leading to early mortality unless treated with bone marrow transplantation [16,17]. Mutations in two human genes, TCIRG1 and CLCN7 (which encodes the ClC-7 protein), together are known to cause ~60% of autosomal recessive osteopetrosis cases.…”

“…A spontaneous mouse model of ARO allowed the identification of a third candidate gene, osteopetrosis associated transmembrane protein 1 (OSTM1) [18]. Subsequently, several human mutations in OSTM1 have been uncovered in ARO patients [16,17]. OSTM1 is a type I transmembrane protein which localizes to intracellular vesicles (mainly endosomes and lysosomes) and homologs have been identified broadly, from humans to Caenorhabditis elegans and Drosophila melanogaster [18].…”

Prognostic potential of precise molecular diagnosis of Autosomal Recessive Osteopetrosis with respect to the outcome of bone marrow transplantation

“…The subset of patients (5% in our cohort) displaying mutations in OSTM1 gene, encoding for a protein involved in late endosomal-lysosomal trafficking, functionally and physically linked to ClCN7 (Lange et al 2006;Meadows et al 2007), is characterized by even more serious neurological defects (neurodegeneration, optic atrophy, microcephaly, cortical atrophy; in one case, bilateral atrial subependymal heterotopias) (Chalhoub et al 2003;Quarello et al 2004;Ramirez et al 2004;Pangrazio et al 2006;Castellano Chiodo et al 2007;Maranda et al 2008). These findings strongly discourage HSCT, because, even if the transplant engrafted, the patient would die due to the severe CNS defects; indeed, in our series no OSTM1-dependent patients have been transplanted.…”