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Molecular Diagnosis of Autosomal Dominant Polycystic Kidney Disease
Published in Jinghua Hu, Yong Yu, Polycystic Kidney Disease, 2019
Matthew Lanktree, Amirreza Haghighi, Xueweng Song, York Pei
Mutation analysis of PKD2 and the single copy region of PKD1 (exon 34–46) is fairly straightforward. Genomic analysis of the remainder of PKD1, including the first (5′) 33 exons, is complicated by the presence of six nearby pseudogenes (PKD1P1-P6) with greater than 98% sequence identity. Incorrectly sequencing pseudogene sequence can lead to both false-positive and false-negative genotype calls, and strategies to avoid this are described below.12 More recently, exome sequencing of families with no mutation detected was employed, resulting in two additional genes having been found to be mutated and causing ADPKD: glucosidase II alpha subunit (GANAB)14 and DNA J heat shock protein family member B11 (DNAJB11).15GANAB was a strong candidate gene for causing kidney cysts because of its function as an endoplasmic reticulum (ER) resident protein required for the maturation and trafficking of membrane proteins including polycystin-1. Mutations in PRKCSH, which encodes the beta subunit of the same glucosidase II protein, cause autosomal dominant polycystic liver disease (ADPLD).16The phenotype in patients with GANAB and DNAJB11 mutations are different than patients with PKD1 or PKD2, with GANAB mutations causing more pronounced polycystic liver disease with a mild kidney phenotype including fewer larger cysts14 and DNAJB11 causing a fibrotic cystic kidney phenotype not associated with kidney enlargement.15 Together, GANAB and DNAJB11 account for less than 1% of ADPKD patients.
Fragment-based screening with natural products for novel anti-parasitic disease drug discovery
Published in Expert Opinion on Drug Discovery, 2019
Fragment-based drug design for host endoplasmic reticulum α-glucosidase II inhibitors for dengue fever treatment used two fragment libraries. One fragment library was constructed from natural products with a Tanimoto similarity of 0.6 to 1-deoxynojirimycin to give 82 (Figure 13). The other Ro3 library gave 83 (Figure 13). The fragments were linked in silico [50].
Pharmacoperone drugs: targeting misfolded proteins causing lysosomal storage-, ion channels-, and G protein-coupled receptors-associated conformational disorders
Published in Expert Review of Clinical Pharmacology, 2018
Zhi-Shuai Hou, Alfredo Ulloa-Aguirre, Ya-Xiong Tao
Nascent proteins fold and assemble in the ER lumen before delivery to other cell compartments [2,38,39]. Unfolded polypeptide chains undergo disulfide bond formation, although it has been recently shown that in single domain proteins folding may precede disulfide bonding [40]. Dimerization, oligomerization, and some other posttranslational modifications (e.g. glycosylation) also occur in the ER [8,39,41]. Folding of proteins is assisted by molecular chaperones, which are key components of the ER QCS, a system that continuously performs surveillance of newly synthesized proteins employing a variety of strategies, including the action of members of the major molecular chaperone families; molecular chaperones are ER-resident proteins that bind to and stabilize unstable conformers to promote correct folding and assembly of the substrate polypeptide [30,42–44]. The presence of non-native determinants indicating that the protein has not achieved a conformation compatible with ER export (e.g. exposure of hydrophobic shapes or particular amino acid sequences, unpaired cysteines or immature glycans) will result in ER retention by the QCS [9,30,34]. For example, the lectin calnexin and its homolog, calreticulin, which bind a broad number of glycoproteins, help folding through the so-called calnexin/calreticulin cycle, which depends on the action of glucosidases I and II, leading to the formation of monoglucosylated oligosaccharide structures and interaction with the chaperones [45–47]. The association terminates when glucosidase II removes the remaining glucose residue from the oligosaccharide chain and the glycoprotein, already in its native conformation, is translocated to the Golgi. However, failure to achieve its native conformation will result in protein retention and successive interaction with the chaperones to ensure that only properly folded proteins reach the Golgi [8,48]. Because the action of calnexin and calreticulin is centered on substrate N-glycans present in the nascent protein, mutations that prevent glycosylation in a glycoprotein will result in a misfolded protein that will fail the quality control checkpoint.