Interaction between hamartin and tuberin, the TSC1 and TSC2 gene products

Slegtenhorst, Marjon van; Nellist, Mark; Nagelkerken, Bas; Cheadle, Jeremy P.; Snell, Russell G.; Ouweland, Ans van den; Reuser, Arnold; Sampson, Julian R.; Halley, Dicky; Sluijs, Peter van der

doi:10.1093/hmg/7.6.1053

Cited by 513 publications

(319 citation statements)

References 14 publications

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“…3,4 These proteins form a heterodimer involved in negative regulation of the mammalian target of rapamycin complex 1 (mTORC1) kinase. [5][6][7] mTORC1 is an important element in controlling cell proliferation and growth, insulin signaling, and protein translation. 8 Dysregulation of mTORC1 is an important aspect in the pathogenesis of TSC.…”

Section: Original Research Article © American College Of Medical Genementioning

confidence: 99%

Self-reported reproductive health in women with tuberous sclerosis complex

Gabitzsch

Hashmi

Koenig

et al. 2013

Genetics in Medicine

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Tuberous sclerosis complex (TSC) is an autosomal-dominant tumor-suppressor disorder characterized by the development of hamartomas in many organ systems. The prevalence of TSC is estimated at 1 in 6,000 individuals, and up to 70% of cases are due to de novo mutation. 1,2 Inactivating mutations in either the TSC1 or TSC2 gene, which encode the proteins hamartin and tuberin, respectively, cause TSC. 3,4 These proteins form a heterodimer involved in negative regulation of the mammalian target of rapamycin complex 1 (mTORC1) kinase. 5-7 mTORC1 is an important element in controlling cell proliferation and growth, insulin signaling, and protein translation. 8 Dysregulation of mTORC1 is an important aspect in the pathogenesis of TSC. 9 Somatic mutation of the second TSC1 or TSC2 allele leads to a loss of heterozygosity, upregulation of mTOR, and dysregulated cellular metabolism. 9 Although virtually any organ can be affected in TSC, the brain, skin, kidneys, heart, and lungs are the principal sites of pathology. TSC shows no ethnic or sex predilection, but interestingly, sex-specific manifestations have been described. Almost 40% of women with TSC develop the pulmonary manifestation lymphangioleiomyomatosis, typically between the ages of 20 and 40 years; most men are unaffected. 10,11 Moreover, the most common renal manifestation, angiomyolipoma, impacts more than 70% of patients, 2 but females are affected an estimated three to four times more often than males. 12 Lymphangioleiomyomatosis and angiomyolipomas share histological features and express estrogen and progesterone receptors, considered important in development. 13 Other effects of sex hormones or reproductive manifestations in TSC are poorly understood.Intriguingly, the role of the TSC1 and TSC2 genes in normal organ function and TSC-associated pathogenesis came to light from the creation of a variety of organ-specific Tsc1-or Tsc2-null animals. Recently, the use of conditional knockout models revealed a role for the murine Tsc1 and Tsc2 genes in the reproductive functioning of the ovary. 14,15 Specifically, these genes are crucial for the maintenance of primordial follicles in a quiescent state and appropriate activation throughout the murine reproductive period. Deletions of either the Tsc1 or Tsc2 gene in the ovaries of mice led to a premature activation of primordial follicles and subsequent depletion of the entire follicular pool, despite initial intact reproductive maturation. The mice essentially experienced what would be defined in humans as premature ovarian insufficiency (POI). POI represents a clear disruption in the normal female reproductive life span and is defined as the cessation of menses in a woman younger than 40 years. POI affects an estimated 1% of the females in the US Purpose: Little is known about sex-specific manifestations of tuberous sclerosis complex. Inactivating mutations in the TSC1 and TSC2 genes cause tuberous sclerosis complex, and recent evidence points to a crucial role for these genes in maintaining appropriate ovarian fun...

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Section: Original Research Article © American College Of Medical Genementioning

confidence: 99%

Self-reported reproductive health in women with tuberous sclerosis complex

Gabitzsch

Hashmi

Koenig

et al. 2013

Genetics in Medicine

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“…TSC1 and TSC2 are widely expressed in human tissues, such as heart, brain, lung, liver, kidney, pancreas and skeletal muscle (Consortium, 1993;van Slegtenhorst et al, 1997;Huang and Manning, 2008). The two proteins interact through coiled-coil domains to form a stable, functional heterodimer (van Slegtenhorst et al, 1998). The C-terminal region of TSC2 shows homology to the Rap GTPase activating protein, and GTPase activating protein activity to various G-proteins (Wienecke et al, 1995;Xiao et al, 1997 NUAK1, NUAK2 SIK1, SIK2 QSK MARK1, MARK2, MARK3, MARK4 BRSK1, BRSK2 SNRK inactive active p la s m a m e m b r a n e Figure 1 Activation and translocation of LKB1.…”

Section: Regulation Of the Tsc1:tsc2 Complexmentioning

confidence: 99%

The long and winding road to rational treatment of cancer associated with LKB1/AMPK/TSC/mTORC1 signaling

et al. 2011

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The liver kinase B1 (LKB1)/adenosine mono-phosphateactivated protein kinase (AMPK)/tuberous sclerosis complex (TSC)/mammalian target of rapamycin (mTOR) complex (mTORC1) cassette constitutes a canonical signaling pathway that integrates information on the metabolic and nutrient status and translates this into regulation of cell growth. Alterations in this pathway are associated with a wide variety of cancers and hereditary hamartoma syndromes, diseases in which hyperactivation of mTORC1 has been described. Specific mTORC1 inhibitors have been developed for clinical use, and these drugs have been anticipated to provide efficient treatment for these diseases. In the present review, we provide an overview of the metabolic LKB1/AMPK/TSC/mTORC1 pathway, describe how its aberrant signaling associates with cancer development, and indicate the difficulties encountered when biochemical data are extrapolated to provide avenues for rational treatment of disease when targeting this signaling pathway. A careful examination of preclinical and clinical studies performed with rapamycin or derivatives thereof shows that although results are encouraging, we are only half way in the long and winding road to design rationale treatment targeted at the LKB1/ AMPK/TSC/mTORC1 pathway. Inherited cancer syndromes associated with this pathway such as the PeutzJeghers syndrome and TSC, provide perfect models to study the relationship between genetics and disease phenotype, and to delineate the complexities that underlie translation of biochemical and genetical information to clinical management, and thus provide important clues for devising novel rational medicine for cancerous diseases in general.

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“…5,28 Mutations were additionally classified into protein-truncating (PT; nonsense, frame-shift, splice site, large deletions of at least one exon) and non-truncating (missense, small in-frame deletions and insertions) mutations. Protein-truncating mutations were divided into proximal and distal mutations, determined from the middle exon of each gene.…”

Section: Genetic Analysismentioning

confidence: 99%

“…3 Mutations in TSC1 and TSC2 are typically inactivating, resulting in little to no protein activity, leading to upregulation of mTORC1. 4,5 This results in a constitutive growth phenotype with development of hamartomas in various organ systems, including the brain. More than 90% of individuals with TSC show neuroanatomical abnormalities such as tubers, sub-ependymal growths and white matter abnormalities.…”

Section: Introductionmentioning

confidence: 99%

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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Interaction between hamartin and tuberin, the TSC1 and TSC2 gene products

Cited by 513 publications

References 14 publications

Self-reported reproductive health in women with tuberous sclerosis complex

Self-reported reproductive health in women with tuberous sclerosis complex

The long and winding road to rational treatment of cancer associated with LKB1/AMPK/TSC/mTORC1 signaling

Genotype and cognitive phenotype of patients with tuberous sclerosis complex

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