Matches in SemOpenAlex for { <https://semopenalex.org/work/W2937555910> ?p ?o ?g. }
- W2937555910 endingPage "2530" @default.
- W2937555910 startingPage "2514" @default.
- W2937555910 abstract "Abstract A rare lysosomal disease resembling a mucopolysaccharidosis with unusual systemic features, including renal disease and platelet dysfunction, caused by the defect in a conserved region of the VPS33A gene on human chromosome 12q24.31, occurs in Yakuts—a nomadic Turkic ethnic group of Southern Siberia. VPS33A is a core component of the class C core vacuole/endosome tethering (CORVET) and the homotypic fusion and protein sorting (HOPS) complexes, which have essential functions in the endocytic pathway. Here we show that cultured fibroblasts from patients with this disorder have morphological changes: vacuolation with disordered endosomal/lysosomal compartments and—common to sphingolipid diseases—abnormal endocytic trafficking of lactosylceramide. Urine glycosaminoglycan studies revealed a pathological excess of sialylated conjugates as well as dermatan and heparan sulphate. Lipidomic screening showed elevated β-D-galactosylsphingosine with unimpaired activity of cognate lysosomal hydrolases. The 3D crystal structure of human VPS33A predicts that replacement of arginine 498 by tryptophan will de-stabilize VPS33A folding. We observed that the missense mutation reduced the abundance of full-length VPS33A and other components of the HOPS and CORVET complexes. Treatment of HeLa cells stably expressing the mutant VPS33A with a proteasome inhibitor rescued the mutant protein from degradation. We propose that the disease is due to diminished intracellular abundance of intact VPS33A. Exposure of patient-derived fibroblasts to the clinically approved proteasome inhibitor, bortezomib, or inhibition of glucosylceramide synthesis with eliglustat, partially corrected the impaired lactosylceramide trafficking defect and immediately suggest therapeutic avenues to explore in this fatal orphan disease." @default.
- W2937555910 created "2019-04-25" @default.
- W2937555910 creator A5008560925 @default.
- W2937555910 creator A5015759748 @default.
- W2937555910 creator A5019746613 @default.
- W2937555910 creator A5023024867 @default.
- W2937555910 creator A5044963259 @default.
- W2937555910 creator A5070496356 @default.
- W2937555910 creator A5075875415 @default.
- W2937555910 creator A5077009289 @default.
- W2937555910 creator A5077487765 @default.
- W2937555910 creator A5080995646 @default.
- W2937555910 creator A5086694434 @default.
- W2937555910 date "2019-04-10" @default.
- W2937555910 modified "2023-10-14" @default.
- W2937555910 title "The lysosomal disease caused by mutant VPS33A" @default.
- W2937555910 cites W1480125634 @default.
- W2937555910 cites W1507071836 @default.
- W2937555910 cites W1534198965 @default.
- W2937555910 cites W1566223979 @default.
- W2937555910 cites W1582892601 @default.
- W2937555910 cites W1588205455 @default.
- W2937555910 cites W1818889225 @default.
- W2937555910 cites W1822005186 @default.
- W2937555910 cites W1914590050 @default.
- W2937555910 cites W1976074435 @default.
- W2937555910 cites W1981606711 @default.
- W2937555910 cites W1987158791 @default.
- W2937555910 cites W1987628482 @default.
- W2937555910 cites W1989742259 @default.
- W2937555910 cites W1994069320 @default.
- W2937555910 cites W1995863785 @default.
- W2937555910 cites W2001692904 @default.
- W2937555910 cites W2004273610 @default.
- W2937555910 cites W2006013727 @default.
- W2937555910 cites W2007108504 @default.
- W2937555910 cites W2007647318 @default.
- W2937555910 cites W2017593971 @default.
- W2937555910 cites W2017903224 @default.
- W2937555910 cites W2023766870 @default.
- W2937555910 cites W2025102169 @default.
- W2937555910 cites W2027343008 @default.
- W2937555910 cites W2032170216 @default.
- W2937555910 cites W2043133278 @default.
- W2937555910 cites W2051226865 @default.
- W2937555910 cites W2055122580 @default.
- W2937555910 cites W2057324561 @default.
- W2937555910 cites W2057437532 @default.
- W2937555910 cites W2073040180 @default.
- W2937555910 cites W2073324353 @default.
- W2937555910 cites W2078659228 @default.
- W2937555910 cites W2079658263 @default.
- W2937555910 cites W2082180699 @default.
- W2937555910 cites W2087703878 @default.
- W2937555910 cites W2099085143 @default.
- W2937555910 cites W2102213696 @default.
- W2937555910 cites W2107277218 @default.
- W2937555910 cites W2108234281 @default.
- W2937555910 cites W2108996658 @default.
- W2937555910 cites W2111626655 @default.
- W2937555910 cites W2116197057 @default.
- W2937555910 cites W2117748535 @default.
- W2937555910 cites W2122947761 @default.
- W2937555910 cites W2123507741 @default.
- W2937555910 cites W2126003136 @default.
- W2937555910 cites W2126782992 @default.
- W2937555910 cites W2127516219 @default.
- W2937555910 cites W2133284292 @default.
- W2937555910 cites W2141520492 @default.
- W2937555910 cites W2142846853 @default.
- W2937555910 cites W2144615875 @default.
- W2937555910 cites W2147057682 @default.
- W2937555910 cites W2159362168 @default.
- W2937555910 cites W2162098634 @default.
- W2937555910 cites W2165934664 @default.
- W2937555910 cites W2186742434 @default.
- W2937555910 cites W2192080449 @default.
- W2937555910 cites W2280662035 @default.
- W2937555910 cites W2299312514 @default.
- W2937555910 cites W2312836697 @default.
- W2937555910 cites W2322556561 @default.
- W2937555910 cites W2401101824 @default.
- W2937555910 cites W2413588516 @default.
- W2937555910 cites W2426816172 @default.
- W2937555910 cites W2486931804 @default.
- W2937555910 cites W2516713727 @default.
- W2937555910 cites W2565640524 @default.
- W2937555910 cites W2580418217 @default.
- W2937555910 cites W2584343751 @default.
- W2937555910 cites W2608335747 @default.
- W2937555910 cites W2751033589 @default.
- W2937555910 cites W2763829738 @default.
- W2937555910 cites W2766363993 @default.
- W2937555910 cites W2950552181 @default.
- W2937555910 cites W2951353377 @default.
- W2937555910 cites W324351088 @default.
- W2937555910 cites W2076527063 @default.
- W2937555910 doi "https://doi.org/10.1093/hmg/ddz077" @default.