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Reduced cell surface levels of GPI‐linked markers in a new case with PIGG loss of function

Glycosylphosphatidylinositol (GPI) is a glycolipid that tethers more than 150 different proteins to the cell surface. Aberrations in biosynthesis of GPI anchors cause congenital disorders of glycosylation with clinical features including intellectual disability (ID), seizures, and facial dysmorphism...

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Autores principales: Zhao, Jin James, Halvardson, Jonatan, Knaus, Alexej, Georgii‐Hemming, Patrik, Baeck, Peter, Krawitz, Peter M., Thuresson, Ann‐Charlotte, Feuk, Lars
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6180480/
https://www.ncbi.nlm.nih.gov/pubmed/28581210
http://dx.doi.org/10.1002/humu.23268
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author Zhao, Jin James
Halvardson, Jonatan
Knaus, Alexej
Georgii‐Hemming, Patrik
Baeck, Peter
Krawitz, Peter M.
Thuresson, Ann‐Charlotte
Feuk, Lars
author_facet Zhao, Jin James
Halvardson, Jonatan
Knaus, Alexej
Georgii‐Hemming, Patrik
Baeck, Peter
Krawitz, Peter M.
Thuresson, Ann‐Charlotte
Feuk, Lars
author_sort Zhao, Jin James
collection PubMed
description Glycosylphosphatidylinositol (GPI) is a glycolipid that tethers more than 150 different proteins to the cell surface. Aberrations in biosynthesis of GPI anchors cause congenital disorders of glycosylation with clinical features including intellectual disability (ID), seizures, and facial dysmorphism. Here, we present two siblings with ID, cerebellar hypoplasia, cerebellar ataxia, early‐onset seizures, and minor facial dysmorphology. Using exome sequencing, we identified a homozygous nonsense variant (NM_001127178.1:c.1640G>A, p.Trp547*) in the gene Phosphatidylinositol Glycan Anchor Biosynthesis, Class G (PIGG) in both the patients. Variants in several other GPI anchor synthesis genes lead to a reduced expression of GPI‐anchored proteins (GPI‐APs) that can be measured by flow cytometry. No significant differences in GPI‐APs could be detected in patient granulocytes, consistent with recent findings. However, fibroblasts showed a reduced global level of GPI anchors and of specific GPI‐linked markers. These findings suggest that fibroblasts might be more sensitive to pathogenic variants in GPI synthesis pathway and are well suited to screen for GPI‐anchor deficiencies. Based on genetic and functional evidence, we confirm that pathogenic variants in PIGG cause an ID syndrome, and we find that loss of function of PIGG is associated with GPI deficiency.
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spelling pubmed-61804802018-10-19 Reduced cell surface levels of GPI‐linked markers in a new case with PIGG loss of function Zhao, Jin James Halvardson, Jonatan Knaus, Alexej Georgii‐Hemming, Patrik Baeck, Peter Krawitz, Peter M. Thuresson, Ann‐Charlotte Feuk, Lars Hum Mutat Research Articles Glycosylphosphatidylinositol (GPI) is a glycolipid that tethers more than 150 different proteins to the cell surface. Aberrations in biosynthesis of GPI anchors cause congenital disorders of glycosylation with clinical features including intellectual disability (ID), seizures, and facial dysmorphism. Here, we present two siblings with ID, cerebellar hypoplasia, cerebellar ataxia, early‐onset seizures, and minor facial dysmorphology. Using exome sequencing, we identified a homozygous nonsense variant (NM_001127178.1:c.1640G>A, p.Trp547*) in the gene Phosphatidylinositol Glycan Anchor Biosynthesis, Class G (PIGG) in both the patients. Variants in several other GPI anchor synthesis genes lead to a reduced expression of GPI‐anchored proteins (GPI‐APs) that can be measured by flow cytometry. No significant differences in GPI‐APs could be detected in patient granulocytes, consistent with recent findings. However, fibroblasts showed a reduced global level of GPI anchors and of specific GPI‐linked markers. These findings suggest that fibroblasts might be more sensitive to pathogenic variants in GPI synthesis pathway and are well suited to screen for GPI‐anchor deficiencies. Based on genetic and functional evidence, we confirm that pathogenic variants in PIGG cause an ID syndrome, and we find that loss of function of PIGG is associated with GPI deficiency. John Wiley and Sons Inc. 2017-06-12 2017-10 /pmc/articles/PMC6180480/ /pubmed/28581210 http://dx.doi.org/10.1002/humu.23268 Text en © 2017 The Authors. Human Mutation published by Wiley Periodicals, Inc. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Research Articles
Zhao, Jin James
Halvardson, Jonatan
Knaus, Alexej
Georgii‐Hemming, Patrik
Baeck, Peter
Krawitz, Peter M.
Thuresson, Ann‐Charlotte
Feuk, Lars
Reduced cell surface levels of GPI‐linked markers in a new case with PIGG loss of function
title Reduced cell surface levels of GPI‐linked markers in a new case with PIGG loss of function
title_full Reduced cell surface levels of GPI‐linked markers in a new case with PIGG loss of function
title_fullStr Reduced cell surface levels of GPI‐linked markers in a new case with PIGG loss of function
title_full_unstemmed Reduced cell surface levels of GPI‐linked markers in a new case with PIGG loss of function
title_short Reduced cell surface levels of GPI‐linked markers in a new case with PIGG loss of function
title_sort reduced cell surface levels of gpi‐linked markers in a new case with pigg loss of function
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6180480/
https://www.ncbi.nlm.nih.gov/pubmed/28581210
http://dx.doi.org/10.1002/humu.23268
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