The role of TREM2 N-glycans in trafficking to the cell surface and signal transduction of TREM2.

Variants of triggering receptor expressed on myeloid cells 2 (TREM2) are associated with an increased incidence of Alzheimer's disease, as well as other neurodegenerative disorders. TREM2 is glycosylated in vitro and in vivo, but the significance of the modification is unknown. We previously established a sensitive and specific reporter cell model involving cultured Jurkat cells stably expressing a luciferase reporter gene and a gene encoding a TREM2DAP12 fusion protein to monitor TREM2-dependent signalling. In the present study, we prepared modified reporter cells to investigate the role of the N-glycans at N20 and N79. We show that the N-glycans at N79 have a requisite role in translocation of TREM2 to the cell surface, while the N-glycans at both N20 and N79 have a critical role in intracellular signal transduction. Our results indicate that structural changes to the TREM2 N-glycans may cause microglial dysfunction that contributes to the pathogenesis of neurodegenerative disorders and that maintaining the integrity of TREM2 N-glycosylation and the responsible glycosyltransferases may be a novel therapeutic strategy to treat these disorders.

Two male siblings with hereditary renal hypouricemia and exercise-induced ARF.

Familial renal hypouricemia with exercise-induced acute renal failure (ARF) is rare. A 45-year-old man presented with abdominal pain, vomiting, and oliguria after severe exercise. The diagnosis was ARF based on high serum creatinine (SCr) level (5.1 mg/dL [451 micromol/L]). Renal function recovered completely within 2 weeks of conservative treatment (creatinine clearance [Ccr], 100.4 mL/min [1.67 mL/s]). After remission, laboratory results showed serum urate (SUA) of 0.8 mg/dL (48 micromol/L), and fractional excretion of uric acid (FE(UA)) of 46%. The final diagnosis was ARF associated with idiopathic renal hypouricemia. Other diseases that could increase the excretion of urate were excluded. Because only mild responses were observed both in pyradinamide and benzbromarone loading tests, he was considered to be a presecretory reabsorption disorder type. The younger brother (42 years old) also had episodes of low and middle back pain after severe exercise and experienced similar attacks at least 5 times since the age of 29. SCr level was elevated in every attack. Hypouricemia (SUA, 1.0 mg/dL [59 micromol/L]) and high urinary urate excretion (FE(UA), 65.7%) also were detected. Renal function recovered almost completely without any specific treatment. Radiologic examination of the 2 cases showed bilateral urolithiasis probably caused by the high urinary urate excretion. Sequence analysis of a urate anion exchanger known to regulate blood urate level (URAT1 gene) in both brothers showed homozygous mutation in exon 4 (W258Stop), resulting in a premature truncated URAT1 protein. Both their parents and their children showed heterozygous mutation of the URAT1 gene. This is the first report of the 2 male siblings of familial renal hypouricemia complicated with exercise-induced ARF, with definite demonstration of genetic abnormality in the responsible gene (URAT1).