A Y328C missense mutation in spermine synthase causes a mild form of 
Snyder-Robinson syndrome

Zhang, Z.; Norris, J.; Kalscheuer, V.; Wood, T.; Wang, L.; Schwartz, C.; Alexov, E.; Van Esch, H.

doi:10.1093/hmg/ddt229

Item

ITEM ACTIONSEXPORT

Add to Basket

Local TagsRelease HistoryDetailsSummary

Released

Journal Article

A Y328C missense mutation in spermine synthase causes a mild form of Snyder-Robinson syndrome

MPS-Authors

/persons/resource/persons50369

Kalscheuer, V.
Chromosome Rearrangements and Disease (Vera Kalscheuer), Dept. of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society;

External Resource

No external resources are shared

Fulltext (restricted access)

There are currently no full texts shared for your IP range.

Fulltext (public)

Zhang.pdf
(Publisher version), 618KB

Supplementary Material (public)

There is no public supplementary material available

Citation

Zhang, Z., Norris, J., Kalscheuer, V., Wood, T., Wang, L., Schwartz, C., et al. (2013). A Y328C missense mutation in spermine synthase causes a mild form of Snyder-Robinson syndrome. Human Molecular Genetics, 22(18), 3789-3797. doi:10.1093/hmg/ddt229.

Cite as: https://hdl.handle.net/11858/00-001M-0000-0018-E930-3

Abstract

Snyder-Robinson syndrome (SRS, OMIM: 309583) is an X-linked intellectual disability (XLID) 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 XLID. 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 with 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 in 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.