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Genetic studies in Drosophila and humans support a model for the concerted function of CISD2, PPT1 and CLN3 in disease

Wolfram syndrome (WFS) is a progressive neurodegenerative disease characterized by diabetes insipidus, diabetes mellitus, optic atrophy, and deafness. WFS1 and WFS2 are caused by recessive mutations in the genes Wolfram Syndrome 1 (WFS1) and CDGSH iron sulfur domain 2 (CISD2), respectively. To explo...

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Autores principales: Jones, Melanie A., Amr, Sami, Ferebee, Aerial, Huynh, Phung, Rosenfeld, Jill A., Miles, Michael F., Davies, Andrew G., Korey, Christopher A., Warrick, John M., Shiang, Rita, Elsea, Sarah H., Girirajan, Santhosh, Grotewiel, Mike
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Company of Biologists 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4021356/
https://www.ncbi.nlm.nih.gov/pubmed/24705017
http://dx.doi.org/10.1242/bio.20147559
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author Jones, Melanie A.
Amr, Sami
Ferebee, Aerial
Huynh, Phung
Rosenfeld, Jill A.
Miles, Michael F.
Davies, Andrew G.
Korey, Christopher A.
Warrick, John M.
Shiang, Rita
Elsea, Sarah H.
Girirajan, Santhosh
Grotewiel, Mike
author_facet Jones, Melanie A.
Amr, Sami
Ferebee, Aerial
Huynh, Phung
Rosenfeld, Jill A.
Miles, Michael F.
Davies, Andrew G.
Korey, Christopher A.
Warrick, John M.
Shiang, Rita
Elsea, Sarah H.
Girirajan, Santhosh
Grotewiel, Mike
author_sort Jones, Melanie A.
collection PubMed
description Wolfram syndrome (WFS) is a progressive neurodegenerative disease characterized by diabetes insipidus, diabetes mellitus, optic atrophy, and deafness. WFS1 and WFS2 are caused by recessive mutations in the genes Wolfram Syndrome 1 (WFS1) and CDGSH iron sulfur domain 2 (CISD2), respectively. To explore the function of CISD2, we performed genetic studies in flies with altered expression of its Drosophila orthologue, cisd2. Surprisingly, flies with strong ubiquitous RNAi-mediated knockdown of cisd2 had no obvious signs of altered life span, stress resistance, locomotor behavior or several other phenotypes. We subsequently found in a targeted genetic screen, however, that altered function of cisd2 modified the effects of overexpressing the fly orthologues of two lysosomal storage disease genes, palmitoyl-protein thioesterase 1 (PPT1 in humans, Ppt1 in flies) and ceroid-lipofuscinosis, neuronal 3 (CLN3 in humans, cln3 in flies), on eye morphology in flies. We also found that cln3 modified the effects of overexpressing Ppt1 in the eye and that overexpression of cln3 interacted with a loss of function mutation in cisd2 to disrupt locomotor ability in flies. Follow-up multi-species bioinformatic analyses suggested that a gene network centered on CISD2, PPT1 and CLN3 might impact disease through altered carbohydrate metabolism, protein folding and endopeptidase activity. Human genetic studies indicated that copy number variants (duplications and deletions) including CLN3, and possibly another gene in the CISD2/PPT1/CLN3 network, are over-represented in individuals with developmental delay. Our studies indicate that cisd2, Ppt1 and cln3 function in concert in flies, suggesting that CISD2, PPT1 and CLN3 might also function coordinately in humans. Further, our studies raise the possibility that WFS2 and some lysosomal storage disorders might be influenced by common mechanisms and that the underlying genes might have previously unappreciated effects on developmental delay.
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spelling pubmed-40213562014-07-15 Genetic studies in Drosophila and humans support a model for the concerted function of CISD2, PPT1 and CLN3 in disease Jones, Melanie A. Amr, Sami Ferebee, Aerial Huynh, Phung Rosenfeld, Jill A. Miles, Michael F. Davies, Andrew G. Korey, Christopher A. Warrick, John M. Shiang, Rita Elsea, Sarah H. Girirajan, Santhosh Grotewiel, Mike Biol Open Research Article Wolfram syndrome (WFS) is a progressive neurodegenerative disease characterized by diabetes insipidus, diabetes mellitus, optic atrophy, and deafness. WFS1 and WFS2 are caused by recessive mutations in the genes Wolfram Syndrome 1 (WFS1) and CDGSH iron sulfur domain 2 (CISD2), respectively. To explore the function of CISD2, we performed genetic studies in flies with altered expression of its Drosophila orthologue, cisd2. Surprisingly, flies with strong ubiquitous RNAi-mediated knockdown of cisd2 had no obvious signs of altered life span, stress resistance, locomotor behavior or several other phenotypes. We subsequently found in a targeted genetic screen, however, that altered function of cisd2 modified the effects of overexpressing the fly orthologues of two lysosomal storage disease genes, palmitoyl-protein thioesterase 1 (PPT1 in humans, Ppt1 in flies) and ceroid-lipofuscinosis, neuronal 3 (CLN3 in humans, cln3 in flies), on eye morphology in flies. We also found that cln3 modified the effects of overexpressing Ppt1 in the eye and that overexpression of cln3 interacted with a loss of function mutation in cisd2 to disrupt locomotor ability in flies. Follow-up multi-species bioinformatic analyses suggested that a gene network centered on CISD2, PPT1 and CLN3 might impact disease through altered carbohydrate metabolism, protein folding and endopeptidase activity. Human genetic studies indicated that copy number variants (duplications and deletions) including CLN3, and possibly another gene in the CISD2/PPT1/CLN3 network, are over-represented in individuals with developmental delay. Our studies indicate that cisd2, Ppt1 and cln3 function in concert in flies, suggesting that CISD2, PPT1 and CLN3 might also function coordinately in humans. Further, our studies raise the possibility that WFS2 and some lysosomal storage disorders might be influenced by common mechanisms and that the underlying genes might have previously unappreciated effects on developmental delay. The Company of Biologists 2014-04-04 /pmc/articles/PMC4021356/ /pubmed/24705017 http://dx.doi.org/10.1242/bio.20147559 Text en © 2014. Published by The Company of Biologists Ltd http://creativecommons.org/licenses/by/3.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
spellingShingle Research Article
Jones, Melanie A.
Amr, Sami
Ferebee, Aerial
Huynh, Phung
Rosenfeld, Jill A.
Miles, Michael F.
Davies, Andrew G.
Korey, Christopher A.
Warrick, John M.
Shiang, Rita
Elsea, Sarah H.
Girirajan, Santhosh
Grotewiel, Mike
Genetic studies in Drosophila and humans support a model for the concerted function of CISD2, PPT1 and CLN3 in disease
title Genetic studies in Drosophila and humans support a model for the concerted function of CISD2, PPT1 and CLN3 in disease
title_full Genetic studies in Drosophila and humans support a model for the concerted function of CISD2, PPT1 and CLN3 in disease
title_fullStr Genetic studies in Drosophila and humans support a model for the concerted function of CISD2, PPT1 and CLN3 in disease
title_full_unstemmed Genetic studies in Drosophila and humans support a model for the concerted function of CISD2, PPT1 and CLN3 in disease
title_short Genetic studies in Drosophila and humans support a model for the concerted function of CISD2, PPT1 and CLN3 in disease
title_sort genetic studies in drosophila and humans support a model for the concerted function of cisd2, ppt1 and cln3 in disease
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4021356/
https://www.ncbi.nlm.nih.gov/pubmed/24705017
http://dx.doi.org/10.1242/bio.20147559
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