Last update 19 Sep 2024
Corneal Dystrophy, Gelatinous Drop-Like
Last update 19 Sep 2024
Basic Info
Synonyms AMYLOID CORNEAL DYSTROPHY, JAPANESE TYPE, AMYLOIDOSIS, CORNEAL, Amyloid corneal dystrophy, Japanese type + [27] |
Introduction An autosomal recessive corneal dystrophy caused by mutation(s) in the TACSTD2 gene, encoding tumor-associated calcium signal transducer 2. It is characterized by severe corneal amyloidosis that may result in blindness. |
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Establishment for in vitro model of gelatinous drop-like corneal dystrophy - In vitro model of gelatinous drop-like corneal dystrophy
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100 Clinical Results associated with Corneal Dystrophy, Gelatinous Drop-Like
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100 Translational Medicine associated with Corneal Dystrophy, Gelatinous Drop-Like
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01 Jan 2024Traffic (Copenhagen, Denmark)
Rescue of secretion of rare-disease-associated misfolded mutant glycoproteins in UGGT1 knock-out mammalian cells.
Article
Author: Gabor Tax ; Kevin P Guay ; Ludovica Pantalone ; Martina Ceci ; Tatiana Soldà ; Charlie J Hitchman ; Johan C Hill ; Snežana Vasiljević ; Andrea Lia ; Carlos P Modenutti ; Kees R Straatman ; Angelo Santino ; Maurizio Molinari ; Nicole Zitzmann ; Daniel N Hebert ; Pietro Roversi ; Marco Trerotola
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.
01 Jun 2023Indian journal of ophthalmology
Repeat deep anterior lamellar keratoplasty (DALK) for failed primary DALK.
Article
Author: Ritu Arora ; Abhilasha Sanoria ; Parul Jain ; Isha Gupta ; Palak Gupta
Purpose:
To evaluate the effectiveness of repeat deep anterior lamellar keratoplasty (DALK) in patients of previous failed DALK.
Methods:
: A retrospective analysis of records of seven patients who had undergone repeat DALK following the failure of the primary DALK was done. The indications for repeat surgery, time elapsed since the first surgery, and pre- & postoperative best-corrected visual acuity (BCVA) were noted for all the patients.
Results:
The follow-up period ranged between one- to four-year post repeat DALK. The indication of primary DALK was keratoconus with vernal keratoconjunctivitis (VKC) (n = 3), corneal amyloidosis (n = 2), Salzman nodular keratopathy (n = 1), and healed keratitis (n = 1). The need for repeat surgery arose when the BSCVA dropped to less than 20/200. The time interval elapsed since the first surgery ranged from two months to four years. Postoperatively, the BSCVA improved from 20/120 to 20/30 at the end of one-year post repeat DALK in all except one patient. All regrafts were clear at the most recent examination, performed after a mean period of 18 months after the secondary graft. No complication was encountered during the resurgery. The dissection of the host bed was easier in the second surgery owing to weaker adhesions.
Conclusion:
The prognosis for repeat DALK for failed DALK is excellent, and the outcomes of secondary grafts were comparable to those of primary DALK grafts. Re DALK offers the advantage of an easier dissection and lower chances of graft rejection compared to penetrating keratoplasty.
31 May 2023bioRxiv : the preprint server for biology
Rescue of secretion of a rare-disease associated mis-folded mutant glycoprotein in UGGT1 knock-out mammalian cells.
Author: Gábor Tax ; Kevin P Guay ; Tatiana Soldà ; Charlie J Hitchman ; Johan C Hill ; Snežana Vasiljević ; Andrea Lia ; Carlos P Modenutti ; Kees R Straatman ; Angelo Santino ; Maurizio Molinari ; Nicole Zitzmann ; Daniel N Hebert ; Pietro Roversi ; Marco Trerotola
Endoplasmic reticulum (ER) retention of mis-folded glycoproteins is mediated by the ER- localised eukaryotic glycoprotein secretion checkpoint, UDP-glucose glycoprotein glucosyl-transferase (UGGT). The enzyme recognises a mis-folded glycoprotein and flags it for ER retention by reglucosylating 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"). Here, we investigated the subcellular localisation of the human Trop-2 Q118E variant, which causes gelatinous drop- like corneal dystrophy (GDLD). Compared with the wild type Trop-2, which is correctly localised at the plasma membrane, the Trop-2-Q118E variant is found to be heavily retained in the ER. Using Trop-2-Q118E, we tested UGGT modulation as a rescue-of-secretion therapeutic strategy for congenital rare disease caused by responsive mutations in genes encoding secreted glycoproteins. We investigated secretion of a EYFP-fusion of Trop-2-Q118E by confocal laser scanning microscopy. As a limiting case of UGGT inhibition, mammalian cells harbouring CRISPR/Cas9-mediated inhibition of the UGGT1 and/or UGGT2 gene expressions were used. The membrane localisation of the Trop-2-Q118E-EYFP mutant was successfully rescued in UGGT1 -/- and UGGT1/2 -/- cells. UGGT1 also efficiently reglucosylated Trop-2-Q118E-EYFP in cellula . The study supports the hypothesis that UGGT1 modulation constitutes a novel therapeutic strategy for the treatment of Trop-2-Q118E associated GDLD, and it encourages the testing of modulators of ER glycoprotein folding Quality Control (ERQC) as broad-spectrum rescue- of-secretion drugs in rare diseases caused by responsive secreted glycoprotein mutants.
Synopsis:
Deletion of the UGGT1 and UGGT1/2 genes in HEK 293T cells rescues secretion of an EYFP-fusion of the human Trop-2-Q118E glycoprotein mutant. The mutant is retained in the secretory pathway in wild type cells and it localises to the cell membrane in UGGT1 -/- single and UGGT1/2 -/- double knock-out cells. The Trop-2-Q118E glycoprotein disease mutant is efficiently glucosylated by UGGT1 in human cells demonstrating that it is a bona fide cellular UGGT1 substrate.
13 Jan 2024
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