Mouse models to investigate the function of spermine.

Many functions have been ascribed to polyamines, but there has been no clear identification of a unique role for spermine. The Gy mouse has a deletion of part of the X chromosome that includes the SMS gene encoding spermine synthase. Tissues from male Gy mice have no spermine but increased spermidine. They have multiple abnormalities including a tendency to sudden death, small size, circling behavior and other neurological symptoms, sterility and deafness. These changes are reversed by breeding with mice expressing a spermine synthase transgene. Detailed studies of hearing in Gy mice show that the absence of spermine synthase leads to loss of the endocochlear potential. Since this potential requires the cochlear lateral wall-specific Kir4.1 channel, regulation by spermine of transport via these channels appears to be an essential function. A similar spermine-related defect in the functioning of cardiac Kir channels could account for arrhythmias leading to sudden death. The effect of the absence of spermine on glutamate receptor ion channels in the brain may account for the neurological symptoms and could contribute to the lack of fertility and normal growth but more direct effects on gene expression are also possible. Advantages and limitations of the Gy model are discussed.