Unusually mild tuberous sclerosis phenotype is associated with<i>TSC2</i>R905Q mutation

Jansen, Anna; Sancak, Őzgür; D’Agostino, Maria Daniela; Badhwar, AmanPreet; Roberts, Penelope; Gobbi, Gabriella; Wilkinson, Ralph D.; Melanson, Denis; Tampieri, Donatella; Koenekoop, Robert K.; Gans, Mark; Maat‐Kievit, Anneke; Goedbloed, Miriam; Ouweland, Ans M.W. van den; Nellist, Mark; Pandolfo, Massimo; McQueen, Mary; Sims, Katherine B.; Thiele, Elisabeth A.; Dubeau, François; Andermann, Frédérick; Kwiatkowski, David J.; Halley, Dicky; Andermann, Eva

doi:10.1002/ana.21037

Cited by 89 publications

(68 citation statements)

References 47 publications

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“…TSC2 patients with proximal PT mutations and HID mutations showed very similar, significantly lower mean IQ/DQs compared with patients with small, in-frame deletions or missense mutations, confirming case reports finding a milder phenotype in patients with missense mutations. 20,22,[29][30][31] This apparent phenotypic dichotomy corresponds with the reported bimodal IQ/DQ distribution in the TSC2 population and we showed that this bimodal appearance can, at least partly, be explained by the effects of different mutation subtypes. Furthermore, these findings correlate well with functional considerations of the effects of different mutations on the TSC1-TSC2 protein complex.…”

Section: Discussionsupporting

confidence: 89%

“…Thus far, no associations have been found between specific TSC mutation types and cognitive outcomes, 10,19 although there are reports on associations with epilepsy and psychiatric features. 10, [19][20][21][22] As most of these studies have limited power or do not address all mutation types of interest, more extensive investigations are warranted to determine potential correlations between genotype and neurocognitive phenotype in TSC. Furthermore, as mTOR-inhibitors are now under investigation to prevent or reverse neurocognitive morbidity in TSC, more specific information on genotype-phenotype associations will assist clinicians and caregivers in these important treatment decisions.…”

Section: Introductionmentioning

confidence: 99%

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Genotype and cognitive phenotype of patients with tuberous sclerosis complex

et al. 2011

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Tuberous sclerosis complex (TSC) is an autosomal dominant, multisystem disorder, which affects 1 in 6000 people. About half of these patients are affected by mental retardation, which has been associated with TSC2 mutations, epilepsy severity and tuber burden. The bimodal intelligence distribution in TSC populations suggests the existence of subgroups with distinct pathophysiologies, which remain to be identified. Furthermore, it is unknown if heterozygous germline mutations in TSC2 can produce the neurocognitive phenotype of TSC independent of epilepsy and tubers. Genotype-phenotype correlations may help to determine risk profiles and select patients for targeted treatments. A retrospective chart review was performed, including a large cohort of 137 TSC patients who received intelligence assessment and genetic mutation analysis. The distribution of intellectual outcomes was investigated for selected genotypes. Genotype-neurocognitive phenotype correlations were performed and associations between specific germline mutations and intellectual outcomes were compared. Results showed that TSC1 mutations in the tuberin interaction domain were significantly associated with lower intellectual outcomes (Po0.03), which was also the case for TSC2 protein-truncating and hamartin interaction domain mutations (both Po0.05). TSC2 missense mutations and small in-frame deletions were significantly associated with higher IQ/DQs (Po0.05). Effects related to the mutation location within the TSC2 gene were found. These findings suggest that TSC2 protein-truncating mutations and small in-frame mutations are associated with distinctly different intelligence profiles, providing further evidence that different types and locations of TSC germline mutations may be associated with distinct neurocognitive phenotypes.

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Genotype and cognitive phenotype of patients with tuberous sclerosis complex

et al. 2011

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“…Previously, we used immunoblotting, double-label immunofluorescent microscopy, in-cell Western analysis, and GAP assays to study the effects of 47 TSC2 missense and in-frame insertions/deletions and 26 TSC1 missense and inframe insertions/deletions on TSC1-TSC2 activity [Coevoets et al, 2009;Jansen et al, 2006Jansen et al, , 2008Mozaffari et al, 2009;Nellist et al, 2005Nellist et al, , 2008Nellist et al, , 2009. Pathogenic missense changes in the N-terminal region of TSC1 (amino acids 50-224) reduced TSC1 stability [Mozaffari et al, 2009;Nellist et al, 2009], while pathogenic TSC2 missense changes had distinct effects on the TSC1-TSC2 complex, depending on the region of TSC2 that was affected.…”

Section: Introductionmentioning

confidence: 99%

Functional assessment of variants in the TSC1 and TSC2 genes identified in individuals with Tuberous Sclerosis Complex

et al. 2011

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The effects of missense changes and small inframe deletions and insertions on protein function are not easy to predict, and the identification of such variants in individuals at risk of a genetic disease can complicate genetic counselling. One option is to perform functional tests to assess whether the variants affect protein function. We have used this strategy to characterize variants identified in the TSC1 and TSC2 genes in individuals with, or suspected of having, Tuberous Sclerosis Complex (TSC). Here we present an overview of our functional studies on 45 TSC1 and 107 TSC2 variants. Using a standardized protocol we classified 16 TSC1 variants and 70 TSC2 variants as pathogenic. In addition we identified eight putative splice site mutations (five TSC1 and three TSC2). The remaining 24 TSC1 and 34 TSC2 variants were classified as probably neutral.

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“…TSC2 missense mutations with apparently mild phenotypic effects have been described previously, 23 -25 and have been shown to affect TSC1 -TSC2 function in vitro. 24,25 In the family shown in Figure 6, it seems most likely that the deletion of exons 1 -8 at the TSC2 locus caused TSC in the fetus. We could not rule out the possibility that the TSC2 R98W substitution modifies the phenotype in this family.…”

Section: Immunoblot Analysis Of the Tsc2 Variantsmentioning

confidence: 99%

A reliable cell-based assay for testing unclassified TSC2 gene variants

et al. 2008

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Tuberous sclerosis complex (TSC) is characterised by seizures, mental retardation and the development of hamartomas in a variety of organs and tissues. The disease is caused by mutations in either the TSC1 gene or the TSC2 gene. The TSC1 and TSC2 gene products, TSC1 and TSC2, form a protein complex that inhibits signal transduction to the downstream effectors of the mammalian target of rapamycin (mTOR). We have developed a straightforward, semiautomated in-cell western (ICW) assay to investigate the effects of amino acid changes on the TSC1 -TSC2-dependent inhibition of mTOR activity. Using this assay, we have characterised 20 TSC2 variants identified in individuals with TSC or suspected of having the disease. In 12 cases, we concluded that the identified variant was pathogenic. The ICW is a rapid, reproducible assay, which can be applied to the characterisation of the effects of novel TSC2 variants on the activity of the TSC1-TSC2 complex.

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Unusually mild tuberous sclerosis phenotype is associated withTSC2R905Q mutation

Cited by 89 publications

References 47 publications

Genotype and cognitive phenotype of patients with tuberous sclerosis complex

Genotype and cognitive phenotype of patients with tuberous sclerosis complex

Functional assessment of variants in the TSC1 and TSC2 genes identified in individuals with Tuberous Sclerosis Complex

A reliable cell-based assay for testing unclassified TSC2 gene variants

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