Growth hormone-deficient dwarfism in the rat: a new mutation

Abstract

Mutations in animals have provided insight into many aspects of normal and pathological human physiology. This paper reports the discovery and initial characterization of a new mutant dwarf rat. The mutation, inherited as an autosomal recessive, arose spontaneously in a breeding colony of Lewis rats at the Medical Research Council Cellular Immunology Unit, Sir William Dunn School of Pathology, Oxford, U.K., in 1985 and the strain has now been established both in Oxford and at Mill Hill. Body growth in the mutant is retarded such that at 3 months of age both males and females weigh approximately 40% less than their normal litter-mates, and continue to grow at a slower rate. The mutants show a selective reduction in pituitary GH synthesis and storage (pituitary GH concentrations were approximately 10% of normal in males and 6% in females). The concentration of their anterior pituitary trophic hormones (LH, TSH, prolactin and ACTH) were within the normal range in dwarf animals. Exogenous GH treatment for 5 days resulted in an increase in growth rate from 1·5 ± 0·3 to 3·9 ± 0·4 g/day in male mutants, and 0·8 ± 0·2 to 3·1 ±0·1 g/day in females. Longitudinal bone growth rates were more than doubled by this treatment from 49 ± 5 to 100 ±10 μm/day in females and from 52 ± 11 to 131 ± 16 μm/day in males. Dot blot and Northern blot analysis of pituitary mRNA extracts revealed that the GH message in mutants was between 20 and 25% of normal, and that the GH transcript was of normal size. Immunoreactive GH-releasing factor (GRF) and somatostatin were present in the dwarf hypothalamus, and exogenous GRF released small amounts of GH in vivo but in proportion to the pituitary GH content. This mutant rat, which shows a selective pituitary GH deficit, may provide a useful new model for studying the endocrinology of growth. J. Endocr. (1988) 119, 51–58