Gene defect mice

FIGURE 23-31 Obesity caused by defective leptin production. Both these mice, which are the same age, have defects in the OB gene. The mouse on the right was provided with purified leptin by daily injection, and weighs 35 g. The mouse on the left got no leptin, consequently ate more food and was less active, and weighs 67 g. 

Lacorazza, H. D., Flax, J. D., Snyder, E. Y. and Jendoubi, M. (1996). Expression of human beta-hexosaminidase alpha-subunit gene (the gene defect of Tay-Sachs disease) in mouse brains upon engraftment of transduced progenitor cells. Nat. Med. 2, 424-429. 

Gwynn B, Ciciotte SL, Hunter SJ, Washburn LL, Smith RS, et al. 2000. Defects in the cappuccino (cno) gene on mouse chromosome 5 and human 4p cause Hermansky-Pudlak syndrome by an AP-3 dependent mechanism. Blood 96 4227-4235. 

On the above view, NLSD is primarily a disease of defective phospholipid metabohsm and the TAG-derived route of phospholipid biosynthesis is essential for the normal functioning of skin, muscle, liver, and the central nervous system. Further studies on the fatty hver dystrophic mouse which bears a close resemblance to human NLSD [103] may identify fhe defective gene. Defective neutral phospholipid metabolism in this mouse model is reflected by a decreased phosphohpid content of peripheral nerve myelin [109]. The nature of the hpase(s) involved in normal TAG-to-phospholipid acyltransfer has not been characterized, but may be similar to a previously described microsomal neutral hpase [110] or to a carboxylesterase [111]. 

In Drosophila, Fat functions as a tumor suppressor gene and dachsous is involved in thorax, leg, and wing development. Several human and mouse homologs have been identified. FAT1 regulates actin filaments, and the Fail knockout leads to defects in glomerular slit formation [3]. 

C1C-3, -4 and -5 form the second branch of the CLC gene family. These proteins are 80% identical, and with the exception of C1C-5, which is most highly expressed in kidney and intestine, show a broad expression pattern. C1C-3 to C1C-5 reside in intracellular membranes of the endocytotic pathway [4]. Disruption of C1C-5 leads to a defect in endocytosis in mouse... 

SUMOl haploinsufficiency has been linlced to a developmental defect Based on the finding that a patient with a cleft lip and palate had a mutation in the SUMOl gene locus, a mouse model was generated that had reduced SUMOl expression. Increased frequency for a cleft palate or oblique facial cleft was observed in the transgenic mice, suggesting that SUMO haploinsufficiency can lead to developmental defects. 

Chisaka, O., and Capecchi. M. R. (1991). Regionally restricted developmental defects resulting from targeted disruption of the mouse homeobox gene hox-1.5. Nature 350 413-419. 

Hodgkinson, C. A Moore, K. J., Nakayama, A., Steingrimmsson, E., Copeland, N. G., Jenkins, N. A., and Amheiter, H. (1993). Mutations at the mouse microphthalmia locus are associated with defects in a gene encoding a novel basic-helix-loop-he-lix-zipper protein. Cell 74 395-404. 

Neuropeptides play key roles in appetite regulation and obesity. Many genes for neuropeptides and neuropeptide receptors have been implicated in obesity and cachexia, anorexia and bulimia [34]. For example,NPY administration into the CNS causes overeating and obesity. A second peptide involved in obesity is leptin, a product of adipocytes and the stomach. The leptin gene is defective in the ob/ob mouse but in normal mice leptin binds to its receptor in the hypothalamus, causing a decrease in the synthesis and release of hypothalamic NPY. 

Two other myosin types have been implicated in hearing and vestibular function [62]. The defect in the Snell s waltzer mouse was found to be a mutation in a myosin VI gene that produces degeneration of the cochlea and vestibular apparatus. Myosin VI is localized to the cuticular plate of the hair cell under stereocilia. Similarly, mutations in a myosin VII gene are responsible for the shaker-1 mouse and several human genetic deafness disorders. This myosin, myosin Vila, is found in a band near the base of the stereocilia distinct from distributions of myosin ip and myosin VI. 

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