Polyamines (
putrescine,
spermidine,
spermine) are ubiquitous, simple molecules that interact with a variety of other molecules in the cell, including
nucleic acids,
phospholipids and
proteins. Various studies indicate that
polyamines are essential for normal cell growth and differentiation. Furthermore, these molecules, especially
spermine, have been shown to modulate
ion channel activities of certain cells. Nonetheless, little is known about the specific cellular functions of these compounds, and extensive laboratory investigations have failed to identify a heritable condition in humans in which
polyamine synthesis is perturbed. We report the first
polyamine deficiency syndrome caused by a defect in
spermine synthase (SMS). The defect results from a splice mutation, and is associated with the
Snyder-Robinson syndrome (SRS, OMIM_309583), an
X-linked mental retardation disorder. The affected males have mild-to-moderate
mental retardation (MR),
hypotonia, cerebellar circuitry dysfunction,
facial asymmetry, thin habitus,
osteoporosis, kyphoscoliosis, decreased activity of SMS, correspondingly low levels of intracellular
spermine in lymphocytes and fibroblasts, and elevated
spermidine/
spermine ratios. The clinical features observed in SRS are consistent with
cerebellar dysfunction and a defective functioning of red nucleus neurons, which, at least in rats, contain high levels of
spermine. Additionally, the presence of MR reflects a role for
spermine in cognitive function, possibly by
spermine's ability to function as an 'intrinsic gateway' molecule for inward rectifier K(+) channels.