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A Novel Missense Mutation in the Mouse Growth Hormone Gene Causes Semidominant Dwarfism, Hyperghrelinemia, and Obesity

Department of Biology/Animal Physiology (C.W.E.M., M.K., S.R., G.H.), Karl-von-Frisch Strasse, Philipps University Marburg, D-35043 Marburg, Germany; Ingenium Pharmaceuticals AG (D.K., W.J., E.C., J.G., M.N.), D-82152 Martinsried, Germany; GSF National Research Center for Environment and Health (H.F., M.H.A.), Institute of Experimental Genetics, D-85764 Oberschleissheim, Germany; Department of Psychiatry (M.T.), Obesity Research Center, University of Cincinnati–Genome Research Institute, Cincinnati, Ohio 45267-0559

Address all correspondence and requests for reprints to: Carola W. E. Meyer, Department of Biology and Animal Physiology, Karl-von-Frisch Strasse, Philipps University Marburg, D-35043 Marburg, Germany. E-mail: meyerc{at}staff.uni-marburg.de.

The SMA1-mouse is a novel ethyl-nitroso-urea (ENU)-induced mouse mutant that carries an ag missense mutation in exon 5 of the GH gene, which translates to a D167G amino acid exchange in the mature protein. Mice carrying the mutation are characterized by dwarfism, predominantly due to the reduction (sma1/+) or absence (sma1/sma1) of the GH-mediated peripubertal growth spurt, with sma1/+ mice displaying a less pronounced phenotype. All genotypes are viable and fertile, and the mode of inheritance is in accordance with a semidominant Mendelian trait. Adult SMA1 mice accumulate excessive amounts of sc and visceral fat in the presence of elevated plasma ghrelin levels, possibly reflecting altered energy partitioning. Our results suggest impaired storage and/or secretion of pituitary GH in mutants, resulting in reduced pituitary GH and reduced GH-stimulated IGF-1 expression. Generation and identification of the SMA1 mouse exemplifies the power of the combination of random mouse mutagenesis with a highly detailed phenotype-analysis as a successful strategy for the detection and analysis of novel gene-function relationships.

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