Table of Contents
1
UI - 11741832
AU - Nellist M; Verhaaf B; Goedbloed MA; Reuser AJ; van den Ouweland AM;
TI -
Halley DJ
TSC2 missense mutations inhibit tuberin phosphorylation and prevent
formation of the tuberin-hamartin complex.
SO - Hum Mol Genet 2001 Dec 1;10(25):2889-98
AD - Department of Clinical Genetics, Erasmus University, 3015 GE Rotterdam,
The Netherlands. nellist@kgen.fgg.eur.nl
Tuberous sclerosis (TSC) is an autosomal dominant disorder characterized
by a broad phenotypic spectrum that includes seizures, mental
retardation, renal dysfunction and dermatological abnormalities.
Inactivating mutations to either of the TSC1 and TSC2 tumour suppressor
genes are responsible for the disease. TSC1 and TSC2 encode two large
novel proteins called hamartin and tuberin, respectively. Hamartin and
tuberin interact directly with each other and it has been reported that
tuberin may act as a chaperone, preventing hamartin self-aggregation and
maintaining the tuberin-hamartin complex in a soluble form. In this
study, the ability of tuberin to act as a chaperone for hamartin was
used to investigate the tuberin-hamartin interaction in more detail. A
domain within tuberin necessary for the chaperone function was
identified, and the effects of TSC2 missense mutations on the
tuberin-hamartin interaction were investigated to allow specific
residues within the central domain of tuberin that are important for the
interaction with hamartin to be pin-pointed. In addition, the results
confirm that phosphorylation may play an important role in the formation
of the tuberin-hamartin complex. Although mutations that prevent tuberin
tyrosine phosphorylation also inhibit tuberin-hamartin binding and the
chaperone function, our results indicate that only hamartin is
phosphorylated in the tuberin-hamartin complex.
2
UI - 11741833
AU - Hodges AK; Li S; Maynard J; Parry L; Braverman R; Cheadle JP; DeClue JE;
TI -
Sampson JR
Pathological mutations in TSC1 and TSC2 disrupt the interaction between
hamartin and tuberin.
SO - Hum Mol Genet 2001 Dec 1;10(25):2899-905
AD - Institute of Medical Genetics, University of Wales College of Medicine,
Heath Park, Cardiff CF14 4XN, UK. hodgesak@cardiff.ac.uk
Critical functions of hamartin and tuberin, encoded by the TSC1 and TSC2
genes, are likely to be closely linked. The proteins interact directly
with one another and mutations affecting either gene result in the
tuberous sclerosis phenotype. However, the regions of hamartin and
tuberin that interact have not been well defined, and the relationship
between their interaction and the pathogenesis of tuberous sclerosis has
not been explored. To address these issues a series of hamartin and
tuberin constructs were used to assay for interaction in the yeast
two-hybrid system. Hamartin (amino acids 302-430) and tuberin (amino
acids 1-418) interacted strongly with one another. A region of tuberin
encoding a putative coiled-coil (amino acids 346-371) was necessary but
not sufficient to mediate the interaction with hamartin, as more
N-terminal residues were also required. A region of hamartin (amino
acids 719-998) predicted to encode coiled-coils was capable of
oligermerization but was not important for the interaction with tuberin.
Subtle, non-truncating mutations identified in patients with tuberous
sclerosis and located within the putative binding regions of hamartin
(N198_F199delinsI;593-595delACT) or tuberin (G294E and I365del),
abolished or dramatically reduced interaction of the proteins as
assessed by yeast two-hybrid assays and by co-immunoprecipitation of the
full-length proteins from Cos7 cells. In contrast, three non-pathogenic
missense polymorphisms of tuberin (R261W, M286V, R367Q) in the same
region as the disease-causing TSC2 mutations did not. These results
indicate a requirement for interaction in critical growth suppressing
functions of hamartin and tuberin.
3
UI - 11774213
AU - Fang L; Wu Z; Wang N; Lin M; Murong S
TI -
[Mutation and polymorphism in exon 4 of tuberous sclerosis complex gene]
SO - Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2001 Dec;18(6):448-51
AD - Department of Neurology, the First Affiliated Hospital of Fujian Medical
University, Fuzhou, Fujian,350005 P.R. China. nwang@163.net
OBJECTIVE: To study the characteristic of mutation and polymorphism in
exon 4 of tuberous sclerosis complex gene(TSC1) in Chinese. METHODS:
Twenty-five TSC patients and 23 parents from 21 families were enrolled.
The mutation of exon 4 in these subjects was identified by polymerase
chain reaction-single strand conformation polymorphism (PCR-SSCP) and
further confirmed by direct sequencing. RESULTS: The normal controls had
the same SSCP bands. In 25 TSC patients, a sporadic case was found to
display variant banding pattern and be heterozygous for 352 insA
mutation by sequencing. In 23 parents who were normal on clinical
examination, another bandshift was found on a mother who had two
affected children, which was confirmed as 347A-->C(Val42Val) single
nucleotide polymorphism(SNP) by sequencing. CONCLUSION: The 352 insA
mutation is a new causative mutation and the 347A-->C is a rare single
nucleotide polymorphism.
4
UI - 11811958
AU - Noonan DJ; Lou D; Griffith N; Vanaman TC
TI -
A calmodulin binding site in the tuberous sclerosis 2 gene product is
essential for regulation of transcription events and is altered by
mutations linked to tuberous sclerosis and lymphangioleiomyomatosis.
SO - Arch Biochem Biophys 2002 Feb 1;398(1):132-40
AD - Department of Biochemistry, University of Kentucky, 800 Rose Street,
Lexington, Kentucky 40536, USA. dnoonan@pop.uky.edu
Mutations in the tuberous sclerosis 2 (TSC2) gene product have been
genetically linked to the pathology of both tuberous sclerosis (TSC) and
the gender-specific lung disease, lymphangioleiomyomatosis (LAM). Both
diseases are classified as disorders of cellular migration,
proliferation, and differentiation. Earlier studies from our laboratory
(1) linked TSC2 with steroid/nuclear receptor signaling. Studies
presented here provide evidence for calmodulin (CaM) signaling in the
propagation of this TSC2 activity. Far Western screening of a lambda
phage human brain cDNA library to identify interacting proteins for the
TSC2 gene product (tuberin) yielded multiple clones encoding human CaM.
Direct binding with 32P-labeled tuberin demonstrated Ca2+-dependent
binding to CaM-Sepharose which was lost upon deletion of the C-terminal
72 residues. The sequence (1740)WIARLRHIKRLRQRIC(1755) was identified as
one capable of forming a basic amphipathic helix indicative of CaM
binding domains in known calmodulin binding proteins. Studies with a
synthetic peptide of this sequence demonstrated very tight
Ca2+-dependent binding to CaM as judged by tryptophan fluorescence
perturbation studies and phosphodiesterase activation by CaM. Deletion
mutagenesis studies further suggested that this CaM binding domain is
required for tuberin modulation of steroid receptor function and that
mutations in this region may be involved in the pathology of TSC and
LAM.
5
UI - 11812941
AU - Martignoni G; Bonetti F; Pea M; Tardanico R; Brunelli M; Eble JN
TI -
Renal disease in adults with TSC2/PKD1 contiguous gene syndrome.
SO - Am J Surg Pathol 2002 Feb;26(2):198-205
AD - Dipartimento di Patologia-Sezione Anatomia Patologica, Policlinico G.B.
Rossi, Universita' di Verona, Via delle Menegone, 10 Verona, 37134
Italy.
The most common renal lesions of tuberous sclerosis complex, an
autosomal-dominant syndrome resulting from losses of TSC1 (9q34) or TSC2
(16p13.3), are renal cysts and angiomyolipomas. Epithelial neoplasms are
less common. The TSC2 gene lies adjacent to PKD1, the major gene
responsible for autosomal-dominant polycystic kidney disease. Recently,
a deletion mutation disrupting both TSC2 and PKD1 has been described in
young children with tuberous sclerosis complex with severe renal cystic
disease. This disease has been termed the TSC2/PKD1 contiguous gene
syndrome. We describe the lesions in the resected kidneys of two adults
with TSC2/PDK1 contiguous gene syndrome, at the time of the
nephrectomies: a 31-year-old man and his 44-year-old mother. The four
kidneys were enlarged reniform masses composed of cysts lined by
flattened, cuboidal, or, infrequently, large deeply eosinophilic
epithelial cells. The kidneys also contained numerous classic
angiomyolipomas and rare intraglomerular microlesions. In the son the
largest tumor was a monotypic epithelioid angiomyolipoma. In the wall of
his left renal pelvis there was a plaque-shaped, HMB-45-positive
localized lesion of lymphangioleiomyomatosis. This is the first
description of the renal lesions in adults with genetically confirmed
TSC2/PDK1 contiguous gene syndrome. The pathologic findings highlight
the importance of thorough sampling for histology in polycystic kidney
diseases and indicate that the observation of an angiomyolipoma in
biopsy material from patients with enlarged cystic kidneys should
suggest the diagnosis of TSC2/PKD1 contiguous gene syndrome, even in
cases without ultrasonographic and macroscopic evidence of
angiomyolipoma.
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