International Mammalian Genome Society

The 14th International Mouse Genome Conference (2000)

Table of Contents * Genes, Physical Mapping and Sequencing * Gene Identification * Bioinformatics * Common Resources * RIKEN Session * Functional Genomics * Complex Traits * Mutagenesis * Developmental Genetics and Differentiation * Verne Chapman Memorial Lecture I and II

A22. The CD4 T Cell Deficient Mouse Mutation nackt (nkt) Involves a Deletion in the Cathepsin L Gene (ctsl)

Benavides F.¹, Painter A. ¹, Poetschke H. ¹, Glasscock E. ¹, Rudensky A. ², Richie E. ¹, Guénet J-L³, Conti C¹.
¹Department of Carcinogenesis, The University of Texas M.D. Anderson Cancer Center, Science Park-Research Division, Smithville, TX 78957, USA;
²Howard Hughes Medical Institute and Department of Immunology, University of Washington School of Medicine, Seattle, WA 98195, USA;
³ Unité de Génétique des Mammifères, Institut Pasteur, 25 rue du Docteur Roux F-75724 Paris, Cedex 15, France

We have recently reported a new mouse mutation named nackt (nkt) affecting the skin and associated with CD4 deficiency. The affected animals show slight growth retardation and diffuse alopecia, although the most striking immunological finding is a marked decrease in the proportion of CD4 T cells in lymphoid tissues. We determined that nkt is an autosomal recessive mutation and mapped the nkt locus to mouse chromosome 13 (Chr 13), 37 cM distal from the centromere. The segment of mouse Chr 13 where the nkt locus was assigned shows homology with human Chr 9q. A recent study reported that ctsl -/- knock-out mice have periodic shedding of fur and anomalous skin morphology, which recapitulate the nackt mutation as well as the old spontaneous mouse mutation furless (fs). Also, ctsl -/- deficient mice show reduced numbers of CD4⁺ T cells in the thymus and periphery (approximately 60 to 80% reduction). The ctsl gene, which is necessary for degradation of Invariant

Chain (Ii), a critical chaperone for MHC class II molecules, in cortical thymic epithelial cells, mapped on mouse Chr 13, in the vicinity of the nackt mutation, and thus was a candidate gene. The present study reports that the nackt mutation comprises a 118 base pair deletion in the ctsl gene (cDNA), involving the end of exon 6 and almost all exon 7, sequences partially coding for the protein heavy and light chain. The data reported here provide further evidence in vivo that the lysosomal cysteine protease cathepsin L has a critical role in the CD4 T cell selection in the thymus.