A Y328C missense mutation in spermine synthase causes a mild form of Snyder-Robinson syndrome
| Autor: | Vera M. Kalscheuer, Emil Alexov, Hilde Van Esch, Charles E. Schwartz, Tim Wood, Joy Norris, Lin Wang, Zhe Zhang |
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| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Adult
Male medicine.medical_specialty Adolescent Spermine Synthase Mutation Missense Spermine Biology PC12 Cells Short stature chemistry.chemical_compound Genes X-Linked Internal medicine Neurites Genetics medicine Animals Humans Missense mutation Molecular Biology Cells Cultured Genetics (clinical) X-linked recessive inheritance Genetic Variation Articles General Medicine Pedigree Rats Spermidine Phenotype Endocrinology chemistry Spermine synthase Mutation (genetic algorithm) Mental Retardation X-Linked biology.protein Hypertonia medicine.symptom |
| Zdroj: | Human Molecular Genetics Europe PubMed Central |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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