Edgetic Perturbations Contribute to Phenotypic Variability in PEX26 Deficiency

Peroxisomes share metabolic pathways with other organelles and peroxisomes are embedded into key cellular processes. However, the specific function of many peroxisomal proteins remains unclear and restricted knowledge of the peroxisomal protein interaction network limits a precise mapping of this ne...

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Autores principales:	Amelie S. Lotz-Havla, Mathias Woidy, Philipp Guder, Jessica Schmiesing, Ralf Erdmann, Hans R. Waterham, Ania C. Muntau, Søren W. Gersting
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	network medicine edgetic perturbations PEX26 BRET peroxisome Genetics QH426-470
Acceso en línea:	https://doaj.org/article/1d918e65f1b043d5b0911c91c23a0f2f
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spelling	oai:doaj.org-article:1d918e65f1b043d5b0911c91c23a0f2f2021-11-04T06:59:10ZEdgetic Perturbations Contribute to Phenotypic Variability in PEX26 Deficiency1664-802110.3389/fgene.2021.726174https://doaj.org/article/1d918e65f1b043d5b0911c91c23a0f2f2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fgene.2021.726174/fullhttps://doaj.org/toc/1664-8021Peroxisomes share metabolic pathways with other organelles and peroxisomes are embedded into key cellular processes. However, the specific function of many peroxisomal proteins remains unclear and restricted knowledge of the peroxisomal protein interaction network limits a precise mapping of this network into the cellular metabolism. Inborn peroxisomal disorders are autosomal or X-linked recessive diseases that affect peroxisomal biogenesis (PBD) and/or peroxisomal metabolism. Pathogenic variants in the PEX26 gene lead to peroxisomal disorders of the full Zellweger spectrum continuum. To investigate the phenotypic complexity of PEX26 deficiency, we performed a combined organelle protein interaction screen and network medicine approach and 1) analyzed whether PEX26 establishes interactions with other peroxisomal proteins, 2) deciphered the PEX26 interaction network, 3) determined how PEX26 is involved in further processes of peroxisomal biogenesis and metabolism, and 4) showed how variant-specific disruption of protein-protein interactions (edgetic perturbations) may contribute to phenotypic variability in PEX26 deficient patients. The discovery of 14 novel protein-protein interactions for PEX26 revealed a hub position of PEX26 inside the peroxisomal interactome. Analysis of edgetic perturbations of PEX26 variants revealed a strong correlation between the number of affected protein-protein interactions and the molecular phenotype of matrix protein import. The role of PEX26 in peroxisomal biogenesis was expanded encompassing matrix protein import, division and proliferation, and membrane assembly. Moreover, the PEX26 interaction network intersects with cellular lipid metabolism at different steps. The results of this study expand the knowledge about the function of PEX26 and refine genotype-phenotype correlations, which may contribute to our understanding of the underlying disease mechanism of PEX26 deficiency.Amelie S. Lotz-HavlaMathias WoidyPhilipp GuderJessica SchmiesingRalf ErdmannHans R. WaterhamAnia C. MuntauSøren W. GerstingFrontiers Media S.A.articlenetwork medicineedgetic perturbationsPEX26BRETperoxisomeGeneticsQH426-470ENFrontiers in Genetics, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	network medicine edgetic perturbations PEX26 BRET peroxisome Genetics QH426-470
spellingShingle	network medicine edgetic perturbations PEX26 BRET peroxisome Genetics QH426-470 Amelie S. Lotz-Havla Mathias Woidy Philipp Guder Jessica Schmiesing Ralf Erdmann Hans R. Waterham Ania C. Muntau Søren W. Gersting Edgetic Perturbations Contribute to Phenotypic Variability in PEX26 Deficiency
description	Peroxisomes share metabolic pathways with other organelles and peroxisomes are embedded into key cellular processes. However, the specific function of many peroxisomal proteins remains unclear and restricted knowledge of the peroxisomal protein interaction network limits a precise mapping of this network into the cellular metabolism. Inborn peroxisomal disorders are autosomal or X-linked recessive diseases that affect peroxisomal biogenesis (PBD) and/or peroxisomal metabolism. Pathogenic variants in the PEX26 gene lead to peroxisomal disorders of the full Zellweger spectrum continuum. To investigate the phenotypic complexity of PEX26 deficiency, we performed a combined organelle protein interaction screen and network medicine approach and 1) analyzed whether PEX26 establishes interactions with other peroxisomal proteins, 2) deciphered the PEX26 interaction network, 3) determined how PEX26 is involved in further processes of peroxisomal biogenesis and metabolism, and 4) showed how variant-specific disruption of protein-protein interactions (edgetic perturbations) may contribute to phenotypic variability in PEX26 deficient patients. The discovery of 14 novel protein-protein interactions for PEX26 revealed a hub position of PEX26 inside the peroxisomal interactome. Analysis of edgetic perturbations of PEX26 variants revealed a strong correlation between the number of affected protein-protein interactions and the molecular phenotype of matrix protein import. The role of PEX26 in peroxisomal biogenesis was expanded encompassing matrix protein import, division and proliferation, and membrane assembly. Moreover, the PEX26 interaction network intersects with cellular lipid metabolism at different steps. The results of this study expand the knowledge about the function of PEX26 and refine genotype-phenotype correlations, which may contribute to our understanding of the underlying disease mechanism of PEX26 deficiency.
format	article
author	Amelie S. Lotz-Havla Mathias Woidy Philipp Guder Jessica Schmiesing Ralf Erdmann Hans R. Waterham Ania C. Muntau Søren W. Gersting
author_facet	Amelie S. Lotz-Havla Mathias Woidy Philipp Guder Jessica Schmiesing Ralf Erdmann Hans R. Waterham Ania C. Muntau Søren W. Gersting
author_sort	Amelie S. Lotz-Havla
title	Edgetic Perturbations Contribute to Phenotypic Variability in PEX26 Deficiency
title_short	Edgetic Perturbations Contribute to Phenotypic Variability in PEX26 Deficiency
title_full	Edgetic Perturbations Contribute to Phenotypic Variability in PEX26 Deficiency
title_fullStr	Edgetic Perturbations Contribute to Phenotypic Variability in PEX26 Deficiency
title_full_unstemmed	Edgetic Perturbations Contribute to Phenotypic Variability in PEX26 Deficiency
title_sort	edgetic perturbations contribute to phenotypic variability in pex26 deficiency
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/1d918e65f1b043d5b0911c91c23a0f2f
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Edgetic Perturbations Contribute to Phenotypic Variability in PEX26 Deficiency

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