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

Nader Chalhoub, Nadia Benachenhou, Venkatesh Rajapurohitam, Monica Pata, Mathieu Ferron, Annalisa Frattini, Anna Villa, Jean Vacher

Research output: Contribution to journalArticlepeer-review


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 GI protein function is absolutely required for osteoclast and melanocyte maturation and function.

Original languageEnglish
Pages (from-to)399-406
Number of pages8
JournalNature Medicine
Issue number4
Publication statusPublished - Apr 1 2003

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)


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