A novel synonymous TSC2 mutation in a Chinese family leads to tuberous sclerosis type 2 by disrupting Normal pre-mRNA splicing.

OBJECTIVE: To explore the molecular mechanism of tuberous sclerosis type 2 caused by TSC2 synonymous mutations affecting normal splicing of precursor mRNA. METHODS: Review and analyses clinical diagnosis and treatment process of a patient with tuberous sclerosis complex type 2, summarize the relationship between genotype and clinical phenotype. Use bioinformatics methods to analyses the effect of TSC2 gene synonymous mutations on precursor mRNA splicing and use in vivo splicing experiments and in vitro minigene experiments to verify the possible pathogenic mechanism of TSC2 gene synonymous mutations. RESULTS: The proband exhibited tuberous sclerosis phenotype including epilepsy and depigmentation. A synonymous mutation in the TSC2 gene (c.1443G > A, p.Glu481=) associated with the phenotype was identified. Bioinformatics analysis suggested that this synonymous mutation may disrupt normal pre-mRNA splicing. Both in vivo splicing assays and minigene experiments confirmed that the synonymous mutation indeed affects proper pre-mRNA splicing. CONCLUSION: TSC2 c.1443G > A (p.Glu481=) synonymous mutation may be associated with tuberous sclerosis type 2 by disrupting normal pre-mRNA splicing.