Disease relevance of TGFBI

• betaig-h3 (TGFBI, keratoepithelin) was first identified as a transforming growth factor-beta1 (TGF-beta1)-inducible gene in a human lung adenocarcinoma cell line [1].
• CONCLUSIONS: Two mutations in the TGFBI gene (A546D and P551Q) cosegregated with LCD in an extensively studied family that lacked the R124C mutation that frequently accompanies this form of corneal amyloidosis [2].
• CONCLUSIONS: We concluded that the TGFBI gene is not responsible for causing keratoconus in these patients [3].
• TGFBI gene mutation analysis in families with hereditary corneal dystrophies from Ukraine [4].
• These results document the expression of beta ig-h3 in diseased human arterial tissue and support the hypothesis that active TGF-beta plays a role in atherogenesis and restenosis [5].

Psychiatry related information on TGFBI

• CSD/BEM localization of P300 sources in adolescents "at-risk": evidence of frontal cortex dysfunction in conduct disorder [6].
• These results indicate that CSD has aversive as well as amnesic properties, there exists a gradient of amnesia, dependent on concentration, and that the cortex is not necessary for learning a taste aversion [7].

High impact information on TGFBI

• This suggests, as the last two diseases are characterized by amyloid deposits, that R124 mutated kerato-epithelin (the product of beta ig-h3) forms amyloidogenic intermediates that precipitate in the cornea [8].
• Granular dystrophy Groenouw type I (CDGG1), Reis-Bücklers (CDRB), lattice type I (CDL1) and Avellino (ACD) are four 5q31-linked human autosomal dominant corneal dystrophies [8].
• In this issue of Neuron, van den Maagdenberg et al. characterize a mouse with a knockin mutation known to cause familial hemiplegic migraine and provide evidence that a lowered threshold to the triggering of CSD may account for the devastating phenotype of familial hemiplegic migraine [9].
• Our data show that the increased susceptibility for CSD and aura in migraine may be due to cortical hyperexcitability [10].
• A kerato-epithelin (betaig-h3) mutation in lattice corneal dystrophy type IIIA [11].

Chemical compound and disease context of TGFBI

• These results suggest that the high glucose-induced beta ig-h3 in VSMCs regulates VSMC functions and may play an important role in diabetic angiopathy [12].
• Two of the SPARC-induced genes, BIGH3 (irreversible by dox) and PAI-1 (reversible by dox) were further studied in additional SPARC-transfected clones, human astrocytoma tissues, and human glioma cell lines by RT-PCR and Northern blot analyses [13].

Biological context of TGFBI

• In reciprocal blocking experiments both proteoglycans inhibited the others binding to beta ig-h3 indicating that they may share the same binding site or that the two binding sites are in close proximity on the beta ig-h3 molecule [14].
• Lastly, it was observed that beta ig-h3-mediated keratinocyte differentiation was caused by promotion of cell adhesion and not by calcium regulation [15].
• Subsequent analysis revealed not only induction of Akt phosphorylation by recombinant beta ig-h3 but also blockage of Akt phosphorylation by LY294002, an inhibitor of phosphatidylinositol 3-kinase [15].
• Six autosomal dominant corneal dystrophies are caused by mutations in the TGFBI (BIGH3) gene on chromosome 5q31: three types of lattice corneal dystrophy (LCD), including type I and type IIIA, granular, Avellino (ACD), and Reis-Bucklers [16].
• We analysed the TGFBI gene by SSCP analysis and direct sequencing in order to further assess the genotype-phenotype correlation [16].

Anatomical context of TGFBI

• Since beta ig-h3 and the SLRPs are known to be associated with the amino-terminal region of collagen VI in tissue microfibrils, the effects of including collagen VI in the incubations were investigated [14].
• MAIN OUTCOME MEASURES: After genomic DNA extraction from peripheral blood leukocytes of each family member, exons of the TGFBI gene were amplified by polymerase chain reaction (PCR), and the PCR products were directly sequenced on both strands [17].
• METHODS: Genomic DNA was extracted from buccal epithelial cells of four affected members of an American family with lattice corneal dystrophy type I. All 17 exons of the TGFBI gene were evaluated by PCR amplification and direct sequencing [18].
• In normal coronary arteries of young individuals, beta ig-h3 protein was absent from the intima and media but was found in the subendothelial smooth muscle cells of some arteries with modest intimal thickening [5].
• A polyclonal antibody consistently immunodetected beta ig-h3 protein in endothelial cells of all vascular tissue [5].

Associations of TGFBI with chemical compounds

• Recombinant beta ig-h3 also promoted keratinocyte adhesion through interaction with integrin alpha3beta1 [15].
• DNA analyses of the TGFBI gene revealed a heterozygous T-->C transition at the second position of codon 540 in exon 12, indicating that replacement of phenylalanine by serine (Phe540Ser) leads to dominant disease [19].
• Twelve members of the family were found to have a heterozygous single mutation in the TGFBI gene leading to a predicted amino acid substitution of aspartic acid for alanine (A546D) [20].
• CONCLUSIONS: Substitution of arginine for leucine at position 569 of the TGFBI gene results in a form of lattice corneal dystrophy that is phenotypically similar to other genetically distinct forms of type I disease [18].
• A heterozygous single base-pair transition (CTG to CGG, leucine to arginin) was detected in codon 527 of the TGFBI gene in both patients [21].

Physical interactions of TGFBI

• Biglycan core protein was shown to inhibit the extent of complexing of beta ig-h3 with native and pepsin-collagen VI suggesting that the glycosaminoglycan side chains of the proteoglycan were important for the formation of the large ternary complexes [14].

Regulatory relationships of TGFBI

• TGF-beta-inducible gene h3 (beta ig-h3) is a novel molecule that is induced when cells are treated with TGF-beta1 [5].
• BIGH3 (TGFBI) Arg124 mutations influence the amyloid conversion of related peptides in vitro [22].

Other interactions of TGFBI

• Co-immunoprecipitation of 125I-labeled biglycan incubated with equimolar mixtures of beta ig-h3 and pepsin-collagen VI was increased 6-fold over beta ig-h3 alone and 3-fold over collagen VI alone [14].
• In the present study, it was demonstrated that expression of both beta ig-h3 and TGF-beta1 was enhanced during keratinocyte differentiation and that expression of the former was strongly induced by that of the latter [15].
• Overall the results indicate that beta ig-h3 can differentially modulate the aggregation of collagen VI with biglycan and decorin [14].
• Beta ig-h3 is an extracellular matrix protein whose expression is highly induced by transforming growth factor (TGF)-beta1 [15].
• A fusion protein composed of the N-terminal 100 amino acids of fibronectin and the RGD-containing C-terminal part of beta ig-h3 was also subjected to C-terminal cleavage and overexpression resulted in apoptosis [23].

Analytical, diagnostic and therapeutic context of TGFBI

• Exons and flanking intron sequences of the TGFBI gene were amplified by PCR with specific primers [24].
• The TGFBI mRNA transcript level was quantitated using Northern blot analysis [25].
• The obtained results show that TGFBI gene mutation analysis is important as well for the early differential diagnosis of corneal dystrophies and genetic consulting in high-risk families [4].
• By using in situ hybridization on fresh directional atherectomy specimens, we found beta ig-h3 mRNA to be overexpressed by plaque macrophages and smooth muscle cells [5].
• Mutations in human BIGH3 (TGFB1), a gene identified after treatment of an adenocarcinoma cell line with TGF-beta, have been observed in patients with granular Groenouw type I, Reis-Bücklers, Thiel-Behnke, Avellino, and Lattice type I and IIIa, six autosomal dominant corneal dystrophies linked to chromosome 5q [26].

References