Transient neuromotor phenotype in transgenic spastic mice expressing low levels of glycine receptor beta-subunit: an animal model of startle disease.
Startle disease or hereditary hyperekplexia has been shown to result from mutations in the alpha1-subunit gene of the inhibitory glycine receptor (GlyR). In hyperekplexia patients, neuromotor symptoms generally become apparent at birth, improve with age, and often disappear in adulthood. Loss-of-function mutations of GlyR alpha or beta-subunits in mice show rather severe neuromotor phenotypes. Here, we generated mutant mice with a transient neuromotor deficiency by introducing a GlyR beta transgene into the spastic mouse (spa/spa), a recessive mutant carrying a transposon insertion within the GlyR beta-subunit gene. In spa/spa TG456 mice, one of three strains generated with this construct, which expressed very low levels of GlyR beta transgene-dependent mRNA and protein, the spastic phenotype was found to depend upon the transgene copy number. Notably, mice carrying two copies of the transgene showed an age-dependent sensitivity to tremor induction, which peaked at approximately 3-4 weeks postnatally. This closely resembles the development of symptoms in human hyperekplexia patients, where motor coordination significantly improves after adolescence. The spa/spa TG456 line thus may serve as an animal model of human startle disease.
Becker
L
L
Institut für Diabetesforschung, Kölner Platz 1, 80804 München, Germany.
Hartenstein
B
B
Schenkel
J
J
Kuhse
J
J
Betz
H
H
Weiher
H
H
D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D003433:Crosses, Genetic; D005260:Female; D005838:Genotype; D006720:Homozygote; D006801:Humans; D006948:Hyperkinesis / Q000235:genetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D018009:Receptors, Glycine / Q000235:genetics* / Q000378:metabolism*; D013216:Reflex, Startle / Q000235:genetics*; D013116:Spinal Cord / Q000378:metabolism*; D014158:Transcription, Genetic; D014202:Tremor / Q000235:genetics* / Q000503:physiopathology
C114561:GLRB protein, human; C491949:Glrb protein, mouse; C491948:Glrb protein, rat; D012333:RNA, Messenger; D018009:Receptors, Glycine