International Mammalian Genome Society

The 14th International Mouse Genome Conference (2000)

B1. The Murine Kyphoscoliosis (ky) Mutant is A Model for Human Idiopathic Scoliosis and is Caused by A Mutation in A Novel Muscle Specific Protein

Gonzalo Blanco1, Gary R. Coulton2, Andrew Biggin2, Christopher Grainge2, Jill Moss3, Michael Barrett3, Anne Berquin4, Georges Maréchal4, Peter van Mier5, Athena Nikitopoulou1, Manfred Kraus1, Chris Ponting6, Roger M. Mason2 and Steve D. M. Brown1
1MRC Mammalian Genetics Unit and UK Mouse Genome Centre, Harwell, Didcot, Oxon OX11 ORD, UK
2Molecular Pathology Group, Division of Biomedical Sciences and
Division of Investigative Sciences, Imperial College School of Medicine, London SW7 2A, UK.
4Departément de Physiologie, Faculté de Médicine, Université de Louvain 5540, 1200 Brussels, Belgium.
5Dept. Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
6MRC Functional Genetics Unit, University of Oxford, Department of Human Anatomy and Genetics, South Parks Road, Oxford OX1 3QX, U.K.

The ky mouse mutant exhibits a primary degenerative myopathy preceding chronic thoraco-lumbar kyphoscoliosis displaying similarities to human scoliotic patients. The ky locus has previously been localised to a small region of mouse chromosome 9. We identified a transcript in this region expressed only in skeletal muscle and heart that is down-regulated in ky/ky mice. Sequencing of this candidate gene in ky/ky mice identified a GC deletion affecting codon 24 downstream of the putative first ATG. The ky gene encodes a novel protein. Database searches have identified homologous proteins in Drosophila melanogaster, Caenorhabditis elegans, Saccharomyces cerevisiae, Schizosaccharomyces pombe and Synechocystis . All these proteins, including ky, contain a domain homologous to human transglutaminase and, with the exception of C. elegans which contains substitutions of key active site residues, these transglutaminase homologues are likely to possess protease functions. The histopathology of the ky mutant suggests that Ky protein activity is crucial for normal muscle growth and function as well as the maturation and stabilization of the neuromuscular junction. Human idiopathic scoliosis, a common group of highly heterogeneous syndromes, is often associated with myopathic pathology. The identification of the ky gene will allow a detailed analysis of the impact of primary myopathy as a cause of idiopathic scoliosis in mice and man.

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