Takehiro Kobayashi

Abnormal Expression of Collagen IV in Lens Activates Unfolded Protein Response Resulting in Cataract

Human diseases caused by mutations in extracellular matrix genes are often associated with an increased risk of cataract and lens capsular rupture. However, the underlying mechanisms of cataract pathogenesis in these conditions are still unknown. Using two different mouse models, we show that the accumulation of collagen chains in the secretory pathway activates the stress signaling pathway termed unfolded protein response (UPR). Transgenic mice expressing ectopic Col4a3 and Col4a4 genes in the lens exhibited activation of IRE1, ATF6, and PERK associated with expansion of the endoplasmic reticulum and attenuation of general protein translation. The expression of the transgenes had adverse effects on lens fiber cell differentiation and eventually induced cell death in a group of transgenic fiber cells. In Col4a1+/Δex40 mutant mice, the accumulation of mutant chains also caused low levels of UPR activation. However, cell death was not induced in mutant lenses, suggesting that low levels of UPR activation are not proapoptotic. Collectively, the results provide in vivo evidence for a role of UPR in cataract formation in response to accumulation of terminally unfolded proteins in the endoplasmic reticulum.

Low Expression of the Deoxycytidine Kinase (dCK) Gene in a 1-β-D- Arabinofuranosylcytosine-Resistant Human Leukemic Cell Line KY-Ra

Molecular change of the deoxycytidine kinase (dCK) gene in a 1-beta-D-arabinofuranosylcytosine-resistant human leukemic cell line (KY-Ra) was investigated. KY-Ra showed the same restriction pattern of genomic DNA and the same nucleotide sequences of the dCK gene as the parental cell line. However, the amount of deoxycytidine kinase mRNA was markedly decreased in KY-Ra compared to the parental cell line. This is the first report showing that the down regulation of dCK gene expression may be affected by a different mechanism than mutation.

HLA‐DQB1 allele associates with idiopathic nephrotic syndrome in Japanese children

HLA‐DQA1 and ‐DQB1 genes were investigated in 30 Japanese children with idiopathic nephrotic syndrome (INS) using the polymerase chain reaction‐restriction fragment length polymorphism method. Compared with control children, there was a significant increase in the HLA‐DQA1 *0501, DQB1 *0301 and DQB1 *0601 alleles, whereas the frequency of DQB1 *0501 showed a significant decrease in the patients. The increase of DQA1 *0501 can be explained as being a result of a linkage disequilibrium with DQB1 *0301. The previous result demonstrating a positive association of DRw6 and DRw8 with INS is also assumed to be attributable to a linkage disequilibrium with DQB1 *0301 and 0601. A total of 83% of patients compared with 37% of controls possessed DQB1 *0301 and/or DQB1 *0601 allele (P < 0.001, RR = 8.6). Only these alleles have alanine at residue 13 and tyrosine at residue 26 in the hypervariable region in the β1 domain of DQB1 gene. These findings suggest that the unique amino acid residues in the DQB1 gene may contribute to disease susceptibility in Japanese children with INS.

Interleukin‐6 polymorphism and bronchopulmonary dysplasia risk in very low‐birthweight infants

Background:u2002 The aim of the present study was to evaluate the role of interleukin (IL)‐6‐634 polymorphism in neonatal disorders such as bronchopulmonary dysplasia (BPD) and periventricular leukomalacia (PVL) in very low‐birthweight (VLBW) infants.

Mutant-type α5(IV) collagen in a mild form of Alport syndrome has residual ability to form a heterotrimer

Alport syndrome (AS) is caused by mutations in type IV collagen α3, α4, and α5 chains. The three chains form a heterotrimer. We have previously shown that all 15 types of recombinant α5(IV) chains with mutations, corresponding to AS mutations, in the noncollagenous (NC1) domain are defective in terms of heterotrimer formation and/or secretion of the heterotrimer from cells. A relatively large family with Cys1638Tyr in the NC1 domain of the α5(IV) chain has been found to have mild AS phenotypes without hearing loss or ocular abnormalities. Renal biopsies of different family members also revealed the presence of the α3(IV), α4(IV), and α5(IV) chains in the glomerular basement membrane. In our study, we introduced the mutation corresponding to Cys1638Tyr into the α5(IV) chain and characterized the mutant chain. In cells containing the mutant-type α5(IV) chain, heterotrimer formation in the cells and secretion of the α5(IV) chain in the monomeric form from the cells were markedly decreased compared with cells containing the wild-type chain. However, the heterotrimer that was formed from the mutant chain was still able to be secreted from the cells. The residual ability of the mutant chain may have led to the unique phenotypes found in the AS family with the Cys1638Tyr mutation.