Rescue of secretion of rare-disease-associated misfolded mutant glycoproteins in UGGT1 knock-out mammalian cells.

Endoplasmic reticulum (ER) retention of misfolded glycoproteins is mediated by the ER-localized eukaryotic glycoprotein secretion checkpoint, UDP-glucose glycoprotein glucosyl-transferase (UGGT). The enzyme recognizes a misfolded glycoprotein and flags it for ER retention by re-glucosylating one of its N-linked glycans. In the background of a congenital mutation in a secreted glycoprotein gene, UGGT-mediated ER retention can cause rare disease, even if the mutant glycoprotein retains activity ("responsive mutant"). Using confocal laser scanning microscopy, we investigated here the subcellular localization of the human Trop-2-Q118E, E227K and L186P mutants, which cause gelatinous drop-like corneal dystrophy (GDLD). Compared with the wild-type Trop-2, which is correctly localized at the plasma membrane, these Trop-2 mutants are retained in the ER. We studied fluorescent chimeras of the Trop-2 Q118E, E227K and L186P mutants in mammalian cells harboring CRISPR/Cas9-mediated inhibition of the UGGT1 and/or UGGT2 genes. The membrane localization of the Trop-2 Q118E, E227K and L186P mutants was successfully rescued in UGGT1-/- cells. UGGT1 also efficiently reglucosylated Trop-2-Q118E-EYFP in cellula. The study supports the hypothesis that UGGT1 modulation would constitute a novel therapeutic strategy for the treatment of pathological conditions associated to misfolded membrane glycoproteins (whenever the mutation impairs but does not abrogate function), and it encourages the testing of modulators of ER glycoprotein folding quality control as broad-spectrum rescue-of-secretion drugs in rare diseases caused by responsive secreted glycoprotein mutants.

Aggressive angiomyxoma of the vulva: case report / Angiomixoma agressivo da vulva: relato de caso

Female patient, 42-years-old, complaining of difficulty in urinating and swelling in the vulvar area for one year. Her gynecological examination showed extensive injury in the vulvar region and the biopsy done was inconclusive. The removal of the lesion was conducted. After the procedure, the patient remains free of recurrence for 15 months. This case highlights the need to consider angiomyxoma in the differential diagnosis for tumors of unknown cause in the vulvar region.

Paciente do gênero feminino, 42 anos, com queixas de dificuldade ao urinar e aumento de volume na região vulvar há 1 ano. Ao exame ginecológico, apresentava extensa lesão na região vulvar. Biópsia da lesão foi inconclusiva. Realizou-se a exérese da lesão. A paciente permanece livre de recorrências há 15 meses. Este caso destaca a necessidade de considerar o angiomixoma no diagnóstico diferencial de massas de causa desconhecida na região vulvar.