Journal of medical genetics · 2015
Intellectual ability in tuberous sclerosis complex correlates with predicted effects of mutations on TSC1 and TSC2 proteins.
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Wong Ho Tin, McCartney Deborah L, Lewis Julia C, Sampson Julian R, Howe Christopher J, de Vries Petrus J
Аннотация
BACKGROUND: Tuberous sclerosis complex is a multisystem genetic disease, caused by mutation in the TSC1 or TSC2 genes, associated with many features, including intellectual disability (ID). We examined psychometric profiles of patients with TSC1 or TSC2 mutations and tested whether different mutation types were associated with different degrees of intellectual ability.
METHODS: One hundred subjects with known TSC1/TSC2 mutations were assessed using a range of IQ or developmental quotient (DQ) measures. Effects of mutations on TSC1/TSC2 proteins were inferred from sequence data and published biochemical studies.
RESULTS: Most individuals with TSC1 mutations fell on a normal distribution identical to the general population, with ∼10% showing profound ID. Of individuals with TSC2 mutations, 34% showed profound ID, and the remainder a pattern of IQ/DQ more variable and shifted to the left than in TSC1 or the general population. Truncating TSC1 mutations were all predicted to be subject to nonsense-mediated mRNA decay. Mutations predicted to result in unstable protein were associated with less severe effects on IQ/DQ. There was a statistically significant negative correlation between length of predicted aberrant C-terminal tails arising from frameshift mutations in TSC1 and IQ/DQ; for TSC2 a positive but not statistically significant correlation was observed.
CONCLUSION: We propose a model where (i) IQ/DQ correlates inversely with predicted levels and/or deleterious biochemical effects of mutant TSC1 or TSC2 protein, and (ii) longer aberrant C-terminal tails arising from frameshift mutations are more detrimental for TSC1 and less for TSC2. Predictions of the model require replication and biochemical testing.
METHODS: One hundred subjects with known TSC1/TSC2 mutations were assessed using a range of IQ or developmental quotient (DQ) measures. Effects of mutations on TSC1/TSC2 proteins were inferred from sequence data and published biochemical studies.
RESULTS: Most individuals with TSC1 mutations fell on a normal distribution identical to the general population, with ∼10% showing profound ID. Of individuals with TSC2 mutations, 34% showed profound ID, and the remainder a pattern of IQ/DQ more variable and shifted to the left than in TSC1 or the general population. Truncating TSC1 mutations were all predicted to be subject to nonsense-mediated mRNA decay. Mutations predicted to result in unstable protein were associated with less severe effects on IQ/DQ. There was a statistically significant negative correlation between length of predicted aberrant C-terminal tails arising from frameshift mutations in TSC1 and IQ/DQ; for TSC2 a positive but not statistically significant correlation was observed.
CONCLUSION: We propose a model where (i) IQ/DQ correlates inversely with predicted levels and/or deleterious biochemical effects of mutant TSC1 or TSC2 protein, and (ii) longer aberrant C-terminal tails arising from frameshift mutations are more detrimental for TSC1 and less for TSC2. Predictions of the model require replication and biochemical testing.