Grey-lethal mutation induces severe malignant autosomal recessive osteopetrosis in mouse and human

Abstract

The spontaneous mouse grey-lethal (gl) mutation is responsible for a coat color defect and for the development of the most severe autosomal recessive form of osteopetrosis. Using a positional cloning approach, we have mapped and isolated the gl locus from a approximately 1.5 cM genetic interval. The gl locus was identified in a bacterial artificial chromosome (BAC) contig by functional genetic complementation in transgenic mice. Genomic sequence analysis revealed that the gl mutation is a deletion resulting in complete loss of function. The unique approximately 3 kb wild-type transcript is expressed primarily in osteoclasts and melanocytes as well as in brain, kidney, thymus and spleen. The gl gene is predicted to encode a 338-amino acid type I transmembrane protein that localizes to the intracellular compartment. Mutation in the human GL gene leads to severe recessive osteopetrosis. Our studies show that mouse Gl protein function is absolutely required for osteoclast and melanocyte maturation and function.

Mutations in SLC45A2 Cause Plumage Color Variation in Chicken and Japanese Quail

“…There are also other mutations found to affect pheomelanin production. The gray-lethal (gl) mouse mutation in the GL/ OSTM1 gene results from stalled pheomelanin migration due to clustered pheomelanin granules (Chalhoub et al 2003), and the g-glutamyl transpeptidase (GGT) knockout mice lack cysteine as a result of the nonworking cleavage of glutathione (Lieberman et al 1996). However, if SLC45A2 has an important role for the incorporation of sulfhydryls into pheomelanin it cannot be its sole function since a defect in cystine/cysteine transport should not affect eumelanogenesis, whereas SLC45A2 null mutations almost completely abolish the production of both eumelanin and pheomelanin.…”

Engraftment and survival following hematopoietic stem cell transplantation for osteopetrosis using a reduced intensity conditioning regimen

“…1,2 More than half of the children with severe OP have mutations in osteoclast-specific H þ -ATPase proton pump A3 subunit (TCIRG1), whereas the second most common genotype is due to recessive mutations in the chloride channel gene, ClCN7. [3][4][5] Other involved genes include isolated reports of rare mutations in the gray lethal gene, 6 as well as abnormalities in the carbonic anhydrase II gene. 7 The deposition of bone by osteoblasts without resorption by osteoclasts results in marked increase in bone density and causes encroachment of bone marrow space resulting in progressive marrow failure and compensatory extramedullary hematopoiesis.…”

Hematological defects in the oc/oc mouse, a model of infantile malignant osteopetrosis

“…The gl mutation consists of a 7.5 kb deletion in the Gl gene encoding a cytoplasmic protein, whose role in OCL is still not clearly established. 6 The Clcn7 À/À mouse displays a disruption of the gene encoding the ClC-7 chloride channel, providing a Cl À conductive pathway that acts in concert with the V-ATPase in electroneutral hydrochloric acid transport during bone resorption. 7 Analysis of the litterature shows that few mutations in the CLCN7 gene [7][8][9] or in the GL gene 6 are associated with IMO, while the vast majority of the patients present mutations in the TCIRG1 gene.…”

“…6 The Clcn7 À/À mouse displays a disruption of the gene encoding the ClC-7 chloride channel, providing a Cl À conductive pathway that acts in concert with the V-ATPase in electroneutral hydrochloric acid transport during bone resorption. 7 Analysis of the litterature shows that few mutations in the CLCN7 gene [7][8][9] or in the GL gene 6 are associated with IMO, while the vast majority of the patients present mutations in the TCIRG1 gene. [10][11][12][13] Therefore, the oc/oc mouse appears to be the most closely resembling model to investigate the physiopathology of the most severe form of human osteopetrosis.…”