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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 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 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.

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Acknowledgements

The authors thank R. McInnes and J. Horsford for melan-a cells; S. Breton for V-ATPase antibodies; D. Bennett for discussion; D. Lohnes and R. Baron for critical reading of the manuscript; U. Ramenghi and families for their participation; J. Marcinkiewicz for advice; and H. Bernard for technical assistance. M.F. has a studentship from the Fonds pour la Formation de Chercheurs et d'Aide à la Recherche (FCAR). This work was supported by a grant from the Canadian Institutes of Health Research and by Hoechst Marion Roussel grant no. R97047 to J.V., partially supported by grant MIUR-FIRB #RBNE019J9W, and is manuscript #71 of the Genoma2000/ITB Project funded by Fondazione Cariplo.

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Correspondence to Jean Vacher.

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Figure 1: Isolation of the mouse gl gene.
Figure 2: Molecular characterization of the gl gene and mutation.
Figure 3: gl expression pattern.
Figure 4: Expression and immunolocalization of the Gl protein.
Figure 5: Alignment of the predicted amino acid sequences of mouse and human Gl proteins (using ClustalW).
Figure 6: DNA and RNA analysis of a patient with infantile malignant osteopetrosis.