Molecular genetic advances in tuberous sclerosis

Cheadle, Jeremy P.; Reeve, Mary Pat; Sampson, Julian R.; Kwiatkowski, David J.

doi:10.1007/s004390000348

Cited by 320 publications

(251 citation statements)

References 125 publications

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“…Interestingly, based on the overall X 2 -values from global tests, the evolutionary-based model was not a better descriptor of the distribution of mutations among regions of this gene. The exceptional pattern observed in this gene relative to the others examined may be due to the fact that, currently only a single functional domain has been identified in TSC2 and, overall very little is known about the true function of the full gene product (Cheadle et al 2000). However, comparative sequence analysis of human and pufferfish TSC2 sequences has revealed additional regions of high conservation (Maheshwar et al 1997), suggesting the presence of additional functional domains.…”

Section: Discussionmentioning

confidence: 88%

“…However, comparative sequence analysis of human and pufferfish TSC2 sequences has revealed additional regions of high conservation (Maheshwar et al 1997), suggesting the presence of additional functional domains. At this time, however, no known homologies to other functional domains have been found (Cheadle et al 2000). Therefore, we grouped all undesignated amino acids at the 5 and 3 ends of the GAP-like domain to create the three gene regions used for analysis purposes.…”

Section: Discussionmentioning

confidence: 99%

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Quantifying the Intragenic Distribution of Human Disease Mutations

Miller

Parker²,

Rissing³

et al. 2003

Annals of Human Genetics

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SummaryA wide variety of functional domains exist within human genes. Since different domains vary in their roles regarding overall gene function, the ability for a mutation in a gene region to produce disease varies among domains. We tested two hypotheses regarding distributions of mutations among functional domains by using (1) sets of single nucleotide disease mutations for six genes (CFTR, TSC2, G6PD, PAX6, RS1, and PAH) and (2) sets of polymorphic replacement and silent mutations found in two genes (CFTR and TSC2). First, we tested the null hypothesis that sets of mutations are uniformly distributed among functional domains within genes. Second, we tested the null hypothesis that disease mutations are distributed among gene regions according to expectations derived from the distribution of evolutionary conserved and variable amino acid sites throughout each gene. In contrast to the mainly uniform distribution of sets of silent and polymorphic mutations, sets of disease mutations generally rejected the null hypotheses of both uniform and evolutionary-influenced distributions. Although the disease mutation data showed a better agreement with the evolutionary-derived expectations, disease mutations were found to be statistically overabundant in conserved domains, and under-represented in variable regions, even after accounting for amino acid site variability of domains over long-term evolutionary history. This finding suggests that there is a nonadditive influence of amino acid site conservation on the observed intragenic distribution of disease mutations, and underscores the importance of understanding the patterns of neutral amino acid substitutions permitted in a gene over long-term evolutionary history.

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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Quantifying the Intragenic Distribution of Human Disease Mutations

Miller

Parker²,

Rissing³

et al. 2003

Annals of Human Genetics

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“…Tuberous sclerosis complex (TSC) is an autosomally inherited disorder with benign tumor formation in the brain, kidney, heart, lung, skin and eye (Cheadle et al, 2000;Dabora et al, 2001). The most frequent manifestation of TSC in the lung is known as lymphangioleiomyomatosis (LAM), a disease that also occurs sporadically (Carsillo et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Rheb activates AMPK and reduces p27Kip1 levels in Tsc2-null cells via mTORC1-independent mechanisms: implications for cell proliferation and tumorigenesis

et al. 2010

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“…22,23 Patients with TSC harbor inactivating mutations involving either TSC1 (hamartin) or TSC2 (tuberin). 24 These genes are targets of AMPK phosphorylation, which will be detailed below. 23 Studies of both PeutzJeghers and TSC have linked alterations of fundamental energy-sensing pathways to the development of human malignancy.…”

Section: Introduction and Historical Perspectivementioning

confidence: 99%

AMP-activated protein kinase and human cancer: cancer metabolism revisited

Kuhajda

2008

Int J Obes

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AMP-activated protein kinase (AMPK) and its upstream kinase, LKB1, act to both monitor and restore cellular energy in response to energy depletion. Studied extensively in liver and skeletal muscle, AMPK is phosphorylated and activated by LKB1 in response to increasing AMP/ATP ratios, which occur in a variety of settings including hypoxia, nutrient starvation and redox imbalance. Interest in the roles of both AMPK and LKB1 in cancer has grown substantially, following the identification of LKB1 as the tumor suppressor gene mutated in the Peutz-Jegher familial cancer syndrome. Patients with the Peutz-Jegher syndrome harbor a single inactive LKB1 gene, and acquisition of a second inactivating lesion (loss of heterozygosity) leads to the development of the cancer in a variety of organs. Thus, the loss of AMPK activation is hypothesized to promote the development of malignancy. Conversely, pharmacological AMPK activation has recently been shown to be cytotoxic to many established human cancer cell lines in vitro and in human cancer xenograft and mouse cancer allografts. Previously, changes in cell metabolism that accompanied the malignant phenotype have largely been considered a consequence of cellular transformation. Now, AMPK and energy metabolism are linked to the development and maintenance of the malignant phenotype. These findings have led to renewed interest in AMPK and cancer cell metabolism in general as potential targets for cancer therapy.

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Molecular genetic advances in tuberous sclerosis

Cited by 320 publications

References 125 publications

Quantifying the Intragenic Distribution of Human Disease Mutations

Quantifying the Intragenic Distribution of Human Disease Mutations

Rheb activates AMPK and reduces p27Kip1 levels in Tsc2-null cells via mTORC1-independent mechanisms: implications for cell proliferation and tumorigenesis

AMP-activated protein kinase and human cancer: cancer metabolism revisited

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