Characterization of the Cytosolic Tuberin-Hamartin Complex

Nellist, Mark; Slegtenhorst, Marjon A. van; Goedbloed, Miriam; Ouweland, Ans M.W. van den; Halley, Dicky; Sluijs, Peter van der

doi:10.1074/jbc.274.50.35647

Cited by 172 publications

(134 citation statements)

References 21 publications

Supporting

Mentioning

111

Contrasting

Unclassified

Order By: Relevance

“…Hamartin interacts with and may function with tuberin to affect cell proliferation (28), its purported chaperone (29), and has also been shown to interact with an N-terminal peptide sequence common to ERM proteins (10). However, expression profiles of ERM proteins do not entirely correlate with the distribution of hamartin in all human tissues.…”

Section: Discussionmentioning

confidence: 99%

Hamartin and Tuberin Expression in Human Tissues

et al. 2001

View full text Add to dashboard Cite

Tuberous sclerosis (TSC) is a bigenic autosomal dominant disease caused by mutations in one of two tumor-suppressor genes, TSC1 and TSC2, resulting in benign hamartomas and low grade neoplasms in multiple organs including brain, heart, kidney, and skin. We report the results of an immunohistochemical study of the expression of the TSC gene products, tuberin and hamartin, in multiple tissues obtained at autopsy from 12 non-TSC affected patients ranging in age from 20 weeks gestation to 8 years, and surgical specimens from some organs. Tuberin and hamartin are expressed and are colocalized in most tissues. Contrary to a previous report, immunostaining with our antisera detected hamartin in liver, small and large intestine, prostate, and testes. We did not detect significant developmental differences in tuberin or hamartin expression in comparable tissues from patients of different ages. Although tuberin and hamartin colocalize in most tissues and cell types, we provide data that hamartin is more abundantly expressed than tuberin in cells within some tissues including the distal nephron and a population of cells of the endocrine pancreas. These data support the hypothesis that hamartin and tuberin interact and may function together in many tissues where they are co-expressed, but also suggest that hamartin has a discrete and specialized function in certain cell types.

show abstract

Section: Discussionmentioning

confidence: 99%

Hamartin and Tuberin Expression in Human Tissues

et al. 2001

View full text Add to dashboard Cite

show abstract

“…There is recent evidence, based on identification of functional protein-protein interactions between hamartin and tuberin, to suggest that hamartin and tuberin comprise a cellular pathway that contributes to cell cycle passage, cell-cell interactions, and possibly cell migration. 41,42 Taken together, these reports imply that mutations in either the TSC1 or TSC2 gene likely results in a downstream cascade of common cellular events that includes changes in neurotrophin expression.…”

Section: Neurotrophin and Tuberin Expressionmentioning

confidence: 99%

Differential Cellular Expression of Neurotrophins in Cortical Tubers of the Tuberous Sclerosis Complex

Kyin

Yang

Baybis

et al. 2001

The American Journal of Pathology

View full text Add to dashboard Cite

Neurotrophins and their receptors modulate cerebral cortical development. Tubers in the tuberous sclerosis complex (TSC) are characterized histologically by disorganized cortical cytoarchitecture and thus, we hypothesized that expression of neurotrophin mRNAs and proteins might be altered in tubers. Using in situ transcription and mRNA amplification to probe cDNA arrays, we found that neurotrophin-3 (NT3) and trkB mRNA expression were reduced whereas neurotrophin-4 (NT4) and trkC mRNA expression were increased in whole tuber sections. Alterations in mRNA abundance were defined in single microdissected dysplastic neurons (DNs) and giant cells (GCs). NT3 mRNA expression was reduced in GCs and trkB mRNA expression was reduced in DNs. NT4 mRNA expression was increased in DNs and trkC mRNA expression was increased in both DNs and GCs. In three patients, TSC2 locus mutations were confirmed and the mean tuberin mRNA expression levels was reduced across all nine cases. Consistent with these observations, NT3 mRNA expression was reduced but trkC mRNA expression was increased in vitro in human NTera2 neurons ( Tubers in the tuberous sclerosis complex (TSC) are developmental abnormalities of cerebral cortical cytoarchitecture that are associated clinically with epilepsy. [1][2][3] Electrocorticography has shown that tubers are epileptogenic and seizures in TSC patients are often medically intractable despite anticonvulsant polytherapy. 4 -6 TSC is an autosomal-dominant disorder resulting from mutations in one of two genes, TSC1 or TSC2 7,8 although the mechanism by which mutations in either TSC gene leads to tuber formation is unknown. Disorganized cortical lamination and aberrant cellular morphology are important histological features of tubers. Large dysplastic neurons (DNs) and giant cells (GCs) are prominent cell types in tubers. 9 DNs and GCs share select morphological features including cytomegaly, the extension of aberrant processes often of unclear identity, ie, axons versus dendrites, and the expression of neural protein markers such as neurofilament and ␣-internexin. 1,9,10 The TSC2 knockout mouse 11 and the Eker rat strain 12 do not fully model human brain pathology in TSC, and thus, analysis of human tuber specimens provides the only direct avenue to study the mechanisms of tuber formation. One strategy to investigate the molecular pathogenesis of cytoarchitectural disorganization in tubers is to evaluate the expression of candidate genes and proteins in human tuber specimens that are relevant to cortical development. 10 Neurotrophins and their cognate receptors comprise a family of proteins that mediate proliferation, differentiation, migration, and process outgrowth during cortical development, 13,14 and thus, are ideal candidate molecules to investigate in tubers. Brainderived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin 3 (NT3), and neurotrophin 4 (NT4) exert their effects on neurons by binding selectively to a family of neuronal cell membrane receptors, trks A to C. 13,14 NGF signals...

show abstract

“…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%

Genotype and cognitive phenotype of patients with tuberous sclerosis complex

et al. 2011

View full text Add to dashboard Cite

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.

show abstract

Characterization of the Cytosolic Tuberin-Hamartin Complex

Cited by 172 publications

References 21 publications

Hamartin and Tuberin Expression in Human Tissues

Hamartin and Tuberin Expression in Human Tissues

Differential Cellular Expression of Neurotrophins in Cortical Tubers of the Tuberous Sclerosis Complex

Genotype and cognitive phenotype of patients with tuberous sclerosis complex

Contact Info

Product

Resources

About