Chubby: a new autosomal recessive skeletal mutation producing dwarfism in the mouse.

Abstract

The chubby (cby) mutant is a previously undescribed skeletal mutation in the mouse. Breeding experiments showed that cby is a recessive mutant with complete viability, full penetrance and fertility in both sexes. Tests for allelism showed that the cby mutant is genetically unlike the somewhat similar mutants, stumpy (stm), pituitary dwarf (dw), spondylometaphyseal chondrodysplasia (smc), brachymorphic (bm), and achondroplasia (cn). The defects seem to occur mainly in growth cartilage. Microradiography revealed increased height of the epiphyseal growth plate and irregular bone trabeculae in the metaphysis. Light microscopy showed disturbed columnar organization of proliferative chondrocytes and pronounced signs of cellular disintegration. The hypertrophic zone, however, contained normally shaped chondrocytes arranged in regular columns. In spite of the normal cellular hypertrophy the pattern of cartilage mineralization was disturbed. The electron microscopy studies revealed very high amounts of matrix vesicles and numerous larger membrane coated structures in the extracellular matrix. Biochemical analysis of the affected growth cartilage revealed a slightly modified pattern of proteoglycan subpopulations and considerably longer chondroitin sulfate chains when compared with controls. From the present study it can be concluded that the cby mutant is a genetically and morphologically distinct condition with characteristic, somewhat rickets-like stigmata. The pathogenetic mechanism underlying the condition remains to be clarified.