Loss-of-function mutations of the
spermine synthase gene (SMS) result in
Snyder-Robinson Syndrome (
SRS), a recessive X-linked syndrome characterized by
intellectual disability,
osteoporosis,
hypotonia, speech abnormalities, kyphoscoliosis, and
seizures. As SMS catalyzes the biosynthesis of the
polyamine spermine from its precursor
spermidine, SMS deficiency causes a lack of
spermine with an accumulation of
spermidine. As
polyamines,
spermine, and
spermidine play essential cellular roles that require tight homeostatic control to ensure normal cell growth, differentiation, and survival. Using patient-derived lymphoblast cell lines, we sought to comprehensively investigate the effects of SMS deficiency on
polyamine homeostatic mechanisms including
polyamine biosynthetic and catabolic
enzymes, derivatives of the natural
polyamines, and
polyamine transport activity. In addition to decreased
spermine and increased
spermidine in SRS cells,
ornithine decarboxylase activity and its product
putrescine were significantly decreased. Treatment of SRS cells with exogenous
spermine revealed that
polyamine transport was active, as the cells accumulated
spermine, decreased their
spermidine level, and established a
spermidine-to-
spermine ratio within the range of wildtype cells. SRS cells also demonstrated elevated levels of
tissue transglutaminase, a change associated with certain
neurodegenerative diseases. These studies form a basis for further investigations into the leading biochemical changes and properties of SMS-mutant cells that potentially represent therapeutic targets for the treatment of
Snyder-Robinson Syndrome.