Missense mutations to the TSC1 gene cause tuberous sclerosis complex

Nellist, Mark; Heuvel, Diana van den; Schluep, Diane; Exalto, Carla; Goedbloed, Miriam; Maat‐Kievit, Anneke; Essen, Ton van; Spaendonck‐Zwarts, Karin van; Jansen, Floor E.; Helderman, P; Bartalini, G.; Vierimaa, Outi; Penttinen, Maila; Ende, Jenneke van den; Ouweland, Ans van den; Halley, Dicky

doi:10.1038/ejhg.2008.170

Cited by 29 publications

(36 citation statements)

References 29 publications

(27 reference statements)

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“…The three patients with splice site mutations in the TID without cognitive impairment were noteworthy and future studies should focus on protein studies of splice site mutations to learn more about their effect. The relatively low mean IQ/DQ of the five TSC1 missense mutations conflicts with previous observations of a relatively mild phenotype, 33,37 possibly due to the fact that all of these missense mutations occurred in the N-terminal region, which is essential for TSC1 function. 32,38 Of note is that, excluding splice site mutations, none of the patients with more distal mutations were affected by MR.…”

Section: Discussioncontrasting

confidence: 96%

“…In contrast, missense and other small in-frame mutations may produce an intact, albeit dysfunctional, protein that remains present in the cell with variable remaining function. 32,33 In addition to this 'all-or-nothing' theory, we found that PT mutations occurring in the latter half of TSC2 were associated with significantly higher intellectual outcomes than PT mutations in the first half of the protein, suggesting that mutations in TSC2 which leave the HID intact may result in production of some functional protein. This suggests a third pathophysiological mechanism, applying to distal TSC2 truncating mutations that leave the HID intact and result in appropriate formation of the hamartin-tuberin complex, but perhaps disrupt functions exerted by domains in the distal part of TSC2, such as GAP-expression, transcription and binding of kinases.…”

Section: Discussionmentioning

confidence: 64%

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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: Discussioncontrasting

confidence: 96%

Section: Discussionmentioning

confidence: 64%

Genotype and cognitive phenotype of patients with tuberous sclerosis complex

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“…In each case, TORC1 activity, as estimated from the ratio of T389 phosphorylated S6K to total S6K, was increased compared to the wild-type control and we classified these variants as pathogenic. Consistent with previous studies [Mozaffari et al, 2009;Nellist et al, 2009], all the variants that were detected at low levels by immunoblotting mapped to the TSC1 N-terminal region (amino acids 50-224) and had a distinct cytoplasmic localization pattern compared to wild-type TSC1, confirming the importance of this region for TSC1 function, localization, and stability [Hoogeveen-Westerveld et al, 2010].…”

Section: Discussionsupporting

confidence: 75%

“…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. Some TSC2 amino acid substitutions prevented TSC1-TSC2 complex formation while others did not affect TSC1-TSC2 binding, but still inactivated the complex .…”

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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“…A reliable functional assay could greatly facilitate the interpretation of variants of uncertain clinical significance. Few TSC1 or TSC2 mutations have been characterized functionally [9][10][11] and it is still impossible to predict phenotypic effects from the location and type of mutation.…”

Section: Introductionmentioning

confidence: 99%

Determining the pathogenicity of patient-derived TSC2 mutations by functional characterization and clinical evidence

et al. 2011

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Tuberous sclerosis complex (TSC) is a genetic condition characterized by the growth of benign tumours in multiple organs, including the brain and kidneys, alongside intellectual disability and seizures. Identification of a causative mutation in TSC1 or TSC2 is important for accurate genetic counselling in affected families, but it is not always clear from genetic data whether a sequence variant is pathogenic or not. In vitro functional analysis could provide support for determining whether an unclassified TSC1 or TSC2 variant is disease-causing. We have performed a detailed functional analysis of four patient-derived TSC2 mutations, E92V, R505Q, H597R and L1624P. One mutant, E92V, functioned similarly to wild-type TSC2, whereas H597R and L1624P had abnormal function in all assays, consistent with available clinical and segregation information. One TSC2 mutation, R505Q, was identified in a patient with intellectual disability, seizures and autistic spectrum disorder but who did not fulfil the diagnostic criteria for TSC. The R505Q mutation was also found in two relatives, one with mild learning difficulties and one without apparent phenotypic abnormality. R505Q TSC2 exhibited partially disrupted function in our assays. These data highlight the difficulties of assessing pathogenicity of a mutation and suggest that multiple lines of evidence, both genetic and functional, are required to assess the pathogenicity of some mutations.

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Missense mutations to the TSC1 gene cause tuberous sclerosis complex

Cited by 29 publications

References 29 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

Determining the pathogenicity of patient-derived TSC2 mutations by functional characterization and clinical evidence

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