Mutation and polymorphism analysis in the tuberous sclerosis 2 ( TSC2 ) gene

Gilbert, John R.; Guy, Vanessa K.; Kumar, Arun; Wolpert, Chantelle M.; Kandt, Raymond S.; Aylesworth, A.; Roses, Allen D.; Pericak‐Vance, M. A.

doi:10.1007/s100480050039

Cited by 15 publications

(15 citation statements)

References 14 publications

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“…The TSC2 F615S substitution was classified as having no known pathogenicity in the TSC2 LOVD, but is a pathogenic change according to our functional assessment, consistent with our previous studies [Nellist et al, 2001. The TSC2 c.1844T4C (p.F615S) variant was identified in an individual with TSC and once in a control group of 4100 apparently unaffected individuals [Gilbert et al, 1998]. However, as far as we are aware, the variant has not been detected in any other individuals.…”

Section: Discussionsupporting

confidence: 89%

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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Section: Discussionsupporting

confidence: 89%

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

et al. 2011

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“…Independent genetic screens of tuberous sclerosis patients have identified dozens of disease-associated lesions spanning virtually the entire length of the Tsc2 protein (43)(44)(45)(46)(47)(48). Several of these mutations, e.g.…”

Section: Discussionmentioning

confidence: 99%

Critical Role of T-Loop and H-Motif Phosphorylation in the Regulation of S6 Kinase 1 by the Tuberous Sclerosis Complex

Shah¹,

Hunter

2004

Journal of Biological Chemistry

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The tuberous sclerosis gene products Tsc1 and Tsc2 behave as tumor suppressors by restricting cell growth, a function conserved among metazoans. Recent evidence has indicated that hyperactivation of S6 kinase 1 (S6K1) may represent an important biochemical change in the development of tuberous sclerosis-associated lesions. We show here that deletion of either Tsc1 or Tsc2 or expression of the Rheb (Ras homolog enriched in brain) GTPase leads to hyperphosphorylation of S6K1 at a subset of regulatory sites, particularly those of two essential residues functionally conserved among AGC superfamily serine/threonine kinases, i.e. the activation loop (T-loop; Thr-229) and the hydrophobic motif (Hmotif; Thr-389). These sites are reciprocally and dose-dependently regulated when S6K1 is coexpressed with the Tsc1-Tsc2 complex. Mutations that render S6K1 mTOR (mammalian target of rapamycin)-resistant also protect S6K1 activity and phosphorylation from down-regulation by Tsc1/2. We demonstrate that two disease-associated mutations in Tsc2 fail to negatively regulate S6K1 activity concomitant with a failure to modify T-loop and H-motif phosphorylation. Finally, we identify one pathological Tsc2 mutation that retains its ability to negatively regulate S6K1, suggesting that, in some cases, tuberous sclerosis may develop independently of S6K1 hyperactivation. These results also highlight the importance of dual control of T-loop and H-motif phosphorylation of S6K1 by the Tsc1-Tsc2 complex.

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“…Three novel missense mutations-p.Phe897Ser, p.Gln1554His and p.Arg1743Trp-were classified as diseaseassociated because the mutant amino acid was absent from the parents. The latter mutation is novel, but p.Arg1743 was previously found to be mutated to Gln or Pro in TSC [Gilbert et al, 1998;Jones et al, 1999]. Finally, the novel p.Arg1570Trp mutation was also classified as disease-associated because the father to the patient had mild TSC symptoms and DNA sequencing suggested mosaicism involving the germline for this mutation.…”

Section: Sequencing Analysis For Small Mutations Intsc1mentioning

confidence: 94%

“…No parental DNA was available for carrier analysis for this mutation. The p.Arg1329His alteration was previously identified by Gilbert et al [1998], but in that study the one parent who was available for analysis tested negative for the mutation. In our study, one of the parents had the mutation, and is currently under examination for minor TSC symptoms.…”

Section: Sequencing Analysis For Small Mutations Intsc1mentioning

confidence: 95%

Analysis of 65 tuberous sclerosis complex (TSC) patients byTSC2DGGE,TSC1/TSC2MLPA, andTSC1long-range PCR sequencing, and report of 28 novel mutations

Rendtorff

Bjerregaard

Frödin³

et al. 2005

Hum. Mutat.

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Tuberous sclerosis complex (TSC) is a severe autosomal-dominant disorder characterized by the development of benign tumors (hamartomas) in many organs. It can lead to intellectual handicap, epilepsy, autism, and renal or heart failure. An inactivating mutation in either of two tumor-suppressor genes-TSC1 and TSC2-is the cause of this syndrome, with TSC2 mutations accounting for 80-90% of all mutations. Molecular diagnosis of TSC is challenging, since TSC1 and TSC2 consist of 21 and 41 coding exons, respectively, and the mutation spectrum is very heterogeneous. Here we report a new approach for detecting mutations in TSC: a denaturing gradient gel electrophoresis (DGGE) analysis for small TSC2 mutations, a multiplex ligation-dependent probe amplification (MLPA) analysis for large deletions and duplications in TSC1 or TSC2, and a long-range PCR/sequencing-based analysis for small TSC1 mutations. When applied in this order, the three methods provide a new sensitive and time- and cost-efficient strategy for the molecular diagnosis of TSC. We analyzed 65 Danish patients who had been clinically diagnosed with TSC, and identified pathogenic mutations in 51 patients (78%). These included 36 small TSC2 mutations, four large deletions involving TSC2, and 11 small TSC1 mutations. Twenty-eight of the small mutations are novel. For the missense mutations, we established a functional assay to demonstrate that the mutations impair TSC2 protein function. In conclusion, the strategy presented may greatly help small- and medium-sized laboratories in the pre- and postnatal molecular diagnosis of TSC.

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Mutation and polymorphism analysis in the tuberous sclerosis 2 ( TSC2 ) gene

Cited by 15 publications

References 14 publications

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

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

Critical Role of T-Loop and H-Motif Phosphorylation in the Regulation of S6 Kinase 1 by the Tuberous Sclerosis Complex

Analysis of 65 tuberous sclerosis complex (TSC) patients byTSC2DGGE,TSC1/TSC2MLPA, andTSC1long-range PCR sequencing, and report of 28 novel mutations

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