A Y328C missense mutation in spermine synthase causes a mild form of Snyder-Robinson syndrome
Zhang, Zhe Norris, Joy Kalscheuer, Vera Wood, Tim Wang, Lin Schwartz, Charles Alexov, Emil Van Esch, Hilde # ×
Human molecular genetics vol:22 issue:18 pages:3789-97
Snyder-Robinson Syndrome (SRS, OMIM: 309583) is an X-linked intellectual disability syndrome, characterized by a collection of clinical features including facial asymmetry, marfanoid habitus, hypertonia, osteoporosis and unsteady gait. It is caused by a significant decrease or loss of spermine synthase (SMS) activity. Here we report a new missense mutation, p.Y328C, (c.1084A>G), in SMS in a family with X-linked intellectual disability. The affected males available for evaluation had mild ID, speech and global delay, an asthenic build, short stature with long fingers and mild kyphosis. The spermine/spermidine ratio in lymphoblasts was 0.53, significantly reduced compared to normal (1.87 average). Activity analysis of SMS in the index patient failed to detect any activity above background. In silico modeling demonstrated that the Y328C mutation has a significant effect on SMS stability, resulting in decreased folding free energy and larger structural fluctuations compared with those of wild type SMS. The loss of activity was attributed to the increase of conformational dynamics in the mutant which affects the active site geometry, rather than preventing dimer formation. Taken together, the biochemical and in silico studies confirm the p.Y328C mutation in SMS is responsible for the patients having a mild form of SRS and reveal yet another molecular mechanism resulting in a non-functional SMS causing SRS.