Protein C-Mannosylation and C-Mannosyl Tryptophan in Chemical Biology and Medicine

C-Mannosylation is a post-translational modification of proteins in the endoplasmic reticulum. Monomeric α-mannose is attached to specific Trp residues at the first Trp in the Trp-x-x-Trp/Cys (W-x-x-W/C) motif of substrate proteins, by the action of C-mannosyltransferases, DPY19-related gene products. The acceptor substrate proteins are included in the thrombospondin type I repeat (TSR) superfamily, cytokine receptor type I family, and others. Previous studies demonstrated that C-mannosylation plays critical roles in the folding, sorting, and/or secretion of substrate proteins. A C-mannosylation-defective gene mutation was identified in humans as the disease-associated variant affecting a C-mannosylation motif of W-x-x-W of ADAMTSL1, which suggests the involvement of defects in protein C-mannosylation in human diseases such as developmental glaucoma, myopia, and/or retinal defects. On the other hand, monomeric C-mannosyl Trp (C-Man-Trp), a deduced degradation product of C-mannosylated proteins, occurs in cells and extracellular fluids. Several studies showed that the level of C-Man-Trp is upregulated in blood of patients with renal dysfunction, suggesting that the metabolism of C-Man-Trp may be involved in human kidney diseases. Together, protein C-mannosylation is considered to play important roles in the biosynthesis and functions of substrate proteins, and the altered regulation of protein C-manosylation may be involved in the pathophysiology of human diseases. In this review, we consider the biochemical and biomedical knowledge of protein C-mannosylation and C-Man-Trp, and introduce recent studies concerning their significance in biology and medicine.

Midterm Results of Microhook ab Interno Trabeculotomy in Initial 560 Eyes with Glaucoma

All the 560 glaucomatous eyes of 375 Japanese subjects (181 men, 194 women; mean age ± standard deviation, 76.0 ± 13.2 years) who underwent microhook ab interno trabeculotomy (µLOT) alone (159 eyes, 28%) or combined µLOT and cataract surgery (401 eyes, 72%) performed by one surgeon at Matsue Red Cross Hospital between May 2015 and March 2018 to control intraocular pressure (IOP) were retrospectively assessed. Preoperative and postoperative IOPs, numbers of antiglaucoma medications, the logarithm of the minimum angle of resolution visual acuity (logMAR VA), anterior chamber (AC) flare, visual field mean deviation (MD), and corneal endothelial cell density (CECD) were compared up to 36 months. Surgical complications and required interventions were described. The duration of the follow-up was 405 ± 327 (range, 2–1326) days. The mean preoperative IOP (20.2 ± 7.0 mmHg) and number of antiglaucoma medications (2.8 ± 1.1) decreased to 13.9 ± 4.5 mmHg (31% reduction, p < 0.0001) and 2.5 ± 1.0 (11% reduction, p < 0.0001), respectively, at the final visit. After combined surgery, compared with preoperatively, the final VA improved 0.11 logMAR (p < 0.0001), AC flare increased 4.5 photon counts/msec (p = 0.0011), MD improved 0.6 decibel (p < 0.0001), and the CECD decreased 6% (p < 0.0001). Layered hyphema (172 eyes, 31%) and hyphema washout (26 eyes, 5%) were the most common postoperative complication and intervention, respectively. At the final visit, 379 (69%) eyes achieved successful IOP control of ≤18 mmHg and ≥20% IOP reduction, and 349 (64%) eyes achieved successful IOP control of ≤15 mmHg and ≥20% IOP reduction. Older age, steroid-induced glaucoma, developmental glaucoma, and the absence of postoperative complications were associated with lower final IOP; exfoliation glaucoma, other types of glaucoma, and higher preoperative IOP were associated with higher final IOP. µLOT has a significant IOP-lowering potential in patients with glaucoma, and improves visual function when combined with cataract surgery.