FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W3105447669> ?p ?o ?g. }

• W3105447669 endingPage "1077" @default.
• W3105447669 startingPage "1062" @default.
• W3105447669 abstract "Dysfunction of the endolysosomal system is often associated with neurodegenerative disease because postmitotic neurons are particularly reliant on the elimination of intracellular aggregates. Adequate function of endosomes and lysosomes requires finely tuned luminal ion homeostasis and transmembrane ion fluxes. Endolysosomal CLC Cl−/H+ exchangers function as electric shunts for proton pumping and in luminal Cl− accumulation. We now report three unrelated children with severe neurodegenerative disease, who carry the same de novo c.1658A>G (p.Tyr553Cys) mutation in CLCN6, encoding the late endosomal Cl−/H+-exchanger ClC-6. Whereas Clcn6−/− mice have only mild neuronal lysosomal storage abnormalities, the affected individuals displayed severe developmental delay with pronounced generalized hypotonia, respiratory insufficiency, and variable neurodegeneration and diffusion restriction in cerebral peduncles, midbrain, and/or brainstem in MRI scans. The p.Tyr553Cys amino acid substitution strongly slowed ClC-6 gating and increased current amplitudes, particularly at the acidic pH of late endosomes. Transfection of ClC-6Tyr553Cys, but not ClC-6WT, generated giant LAMP1-positive vacuoles that were poorly acidified. Their generation strictly required ClC-6 ion transport, as shown by transport-deficient double mutants, and depended on Cl−/H+ exchange, as revealed by combination with the uncoupling p.Glu200Ala substitution. Transfection of either ClC-6Tyr553Cys/Glu200Ala or ClC-6Glu200Ala generated slightly enlarged vesicles, suggesting that p.Glu200Ala, previously associated with infantile spasms and microcephaly, is also pathogenic. Bafilomycin treatment abrogated vacuole generation, indicating that H+-driven Cl− accumulation osmotically drives vesicle enlargement. Our work establishes mutations in CLCN6 associated with neurological diseases, whose spectrum of clinical features depends on the differential impact of the allele on ClC-6 function." @default.
• W3105447669 created "2020-11-23" @default.
• W3105447669 creator A5001377500 @default.
• W3105447669 creator A5002158250 @default.
• W3105447669 creator A5008953665 @default.
• W3105447669 creator A5016899192 @default.
• W3105447669 creator A5024967273 @default.
• W3105447669 creator A5028906199 @default.
• W3105447669 creator A5029377107 @default.
• W3105447669 creator A5030521427 @default.
• W3105447669 creator A5036358608 @default.
• W3105447669 creator A5036727139 @default.
• W3105447669 creator A5038427804 @default.
• W3105447669 creator A5048934823 @default.
• W3105447669 creator A5050091481 @default.
• W3105447669 creator A5052993222 @default.
• W3105447669 creator A5056644612 @default.
• W3105447669 creator A5061382460 @default.
• W3105447669 creator A5062729918 @default.
• W3105447669 creator A5075037256 @default.
• W3105447669 creator A5086437333 @default.
• W3105447669 creator A5087472564 @default.
• W3105447669 date "2020-12-01" @default.
• W3105447669 modified "2023-10-14" @default.
• W3105447669 title "A Recurrent Gain-of-Function Mutation in CLCN6, Encoding the ClC-6 Cl−/H+-Exchanger, Causes Early-Onset Neurodegeneration" @default.
• W3105447669 cites W119876498 @default.
• W3105447669 cites W1494114085 @default.
• W3105447669 cites W1545907911 @default.
• W3105447669 cites W1592962814 @default.
• W3105447669 cites W1782667879 @default.
• W3105447669 cites W1808711893 @default.
• W3105447669 cites W1965620778 @default.
• W3105447669 cites W1969432236 @default.
• W3105447669 cites W1972555987 @default.
• W3105447669 cites W1982831381 @default.
• W3105447669 cites W1992848235 @default.
• W3105447669 cites W1994088425 @default.
• W3105447669 cites W2000197503 @default.
• W3105447669 cites W2005416997 @default.
• W3105447669 cites W2010103693 @default.
• W3105447669 cites W2017972396 @default.
• W3105447669 cites W2020529024 @default.
• W3105447669 cites W2027978484 @default.
• W3105447669 cites W2028127482 @default.
• W3105447669 cites W2030338986 @default.
• W3105447669 cites W2030929739 @default.
• W3105447669 cites W2032499946 @default.
• W3105447669 cites W2041455826 @default.
• W3105447669 cites W2046499002 @default.
• W3105447669 cites W2053191479 @default.
• W3105447669 cites W2064339678 @default.
• W3105447669 cites W2071862987 @default.
• W3105447669 cites W2076233064 @default.
• W3105447669 cites W2076831743 @default.
• W3105447669 cites W2080405368 @default.
• W3105447669 cites W2082732734 @default.
• W3105447669 cites W2085186575 @default.
• W3105447669 cites W2085536739 @default.
• W3105447669 cites W2087391996 @default.
• W3105447669 cites W2088894092 @default.
• W3105447669 cites W2093649371 @default.
• W3105447669 cites W2097243253 @default.
• W3105447669 cites W2102661252 @default.
• W3105447669 cites W2103104037 @default.
• W3105447669 cites W2105404023 @default.
• W3105447669 cites W2105525143 @default.
• W3105447669 cites W2106538910 @default.
• W3105447669 cites W2109690069 @default.
• W3105447669 cites W2122901539 @default.
• W3105447669 cites W2124376775 @default.
• W3105447669 cites W2131856606 @default.
• W3105447669 cites W2133281929 @default.
• W3105447669 cites W2134830857 @default.
• W3105447669 cites W2135453787 @default.
• W3105447669 cites W2162362319 @default.
• W3105447669 cites W2164797647 @default.
• W3105447669 cites W2166911293 @default.
• W3105447669 cites W2171130490 @default.
• W3105447669 cites W2178323098 @default.
• W3105447669 cites W2402185687 @default.
• W3105447669 cites W2579085839 @default.
• W3105447669 cites W2802498898 @default.
• W3105447669 cites W2803610788 @default.
• W3105447669 cites W2805997389 @default.
• W3105447669 cites W2889090388 @default.
• W3105447669 cites W2891723330 @default.
• W3105447669 cites W2928439698 @default.
• W3105447669 cites W2947122456 @default.
• W3105447669 cites W2952247784 @default.
• W3105447669 cites W2969827363 @default.
• W3105447669 cites W2981894238 @default.
• W3105447669 cites W2994423700 @default.
• W3105447669 cites W3010165610 @default.
• W3105447669 cites W3020893188 @default.
• W3105447669 cites W3047453426 @default.
• W3105447669 cites W3048520407 @default.
• W3105447669 cites W52925546 @default.
• W3105447669 doi "https://doi.org/10.1016/j.ajhg.2020.11.004" @default.

• next