Bi-allelic variants in NAE1 cause intellectual disability, ischiopubic hypoplasia, stress-mediated lymphopenia and neurodegeneration
- Autores
- Muffels, Irena J. J.; Schene, Imre F.; Rehmann, Holger; Massink, Maarten P. G.; van der Wal, Maria M.; Bauder, Corinna; Labeur, Martha; Armando, Natalia Giannina; Lequin, Maarten H.; Houben, Michiel L.; Giltay, Jaques C.; Haitjema, Saskia; Huisman, Albert; Vansenne, Fleur; Bluvstein, Judith; Pappas, John; Shailee, Lala V.; Zarate, Yuri A.; Mokry, Michal; van Haaften, Gijs W.; Nieuwenhuis, Edward E.S.; Refojo, Damian; van Wijk, Femke; Fuchs, Sabine A.; van Hasselt, Peter M.
- Año de publicación
- 2023
- Idioma
- inglés
- Tipo de recurso
- artículo
- Estado
- versión publicada
- Descripción
- Neddylation has been implicated in various cellular pathways and in the pathophysiology of numerous diseases. We identified four individuals with bi-allelic variants in NAE1, which encodes the neddylation E1 enzyme. Pathogenicity was supported by decreased NAE1 abundance and overlapping clinical and cellular phenotypes. To delineate how cellular consequences of NAE1 deficiency would lead to the clinical phenotype, we focused primarily on the rarest phenotypic features, based on the assumption that these would best reflect the pathophysiology at stake. Two of the rarest features, neuronal loss and lymphopenia worsening during infections, suggest that NAE1 is required during cellular stress caused by infections to protect against cell death. In support, we found that stressing the proteasome system with MG132—requiring upregulation of neddylation to restore proteasomal function and proteasomal stress—led to increased cell death in fibroblasts of individuals with NAE1 genetic variants. Additionally, we found decreased lymphocyte counts after CD3/CD28 stimulation and decreased NF-κB translocation in individuals with NAE1 variants. The rarest phenotypic feature—delayed closure of the ischiopubic rami—correlated with significant downregulation of RUN2X and SOX9 expression in transcriptomic data of fibroblasts. Both genes are involved in the pathophysiology of ischiopubic hypoplasia. Thus, we show that NAE1 plays a major role in (skeletal) development and cellular homeostasis during stress. Our approach suggests that a focus on rare phenotypic features is able to provide significant pathophysiological insights in diseases caused by mutations in genes with pleiotropic effects.
Fil: Muffels, Irena J. J.. Utrecht University; Países Bajos
Fil: Schene, Imre F.. Utrecht University; Países Bajos
Fil: Rehmann, Holger. Flensburg University of Applied Sciences; Alemania
Fil: Massink, Maarten P. G.. Utrecht University; Países Bajos
Fil: van der Wal, Maria M.. Utrecht University; Países Bajos
Fil: Bauder, Corinna. Helmholtz Zentrum München; Alemania. Helmholtz Centre for Environmental Research; Alemania
Fil: Labeur, Martha. Helmholtz Centre for Environmental Research; Alemania
Fil: Armando, Natalia Giannina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina
Fil: Lequin, Maarten H.. Utrecht University; Países Bajos
Fil: Houben, Michiel L.. Utrecht University; Países Bajos
Fil: Giltay, Jaques C.. Utrecht University; Países Bajos
Fil: Haitjema, Saskia. Utrecht University; Países Bajos
Fil: Huisman, Albert. Utrecht University; Países Bajos
Fil: Vansenne, Fleur. University of Groningen; Países Bajos
Fil: Bluvstein, Judith. NYU School of Medicine; Estados Unidos
Fil: Pappas, John. NYU School of Medicine; Estados Unidos
Fil: Shailee, Lala V.. NYU School of Medicine; Estados Unidos
Fil: Zarate, Yuri A.. University of Arkansas for Medical Sciences; Estados Unidos
Fil: Mokry, Michal. Utrecht University; Países Bajos
Fil: van Haaften, Gijs W.. Utrecht University; Países Bajos
Fil: Nieuwenhuis, Edward E.S.. University College Roosevelt; Países Bajos
Fil: Refojo, Damian. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina. Max Planck Institute of Psychiatry; Alemania
Fil: van Wijk, Femke. Utrecht University; Países Bajos
Fil: Fuchs, Sabine A.. Utrecht University; Países Bajos
Fil: van Hasselt, Peter M.. Utrecht University; Países Bajos - Materia
-
LYMPHOPENIA
NAE1
NEDDYLATION
NEURODEGENERATION
OCURRENCE RATIO
PHENOTYPIC SPECIFICITY
POST-TRANSLATIONAL PROTEIN MODIFICATION
PROTEASOME
UBIQUITINATION - Nivel de accesibilidad
- acceso abierto
- Condiciones de uso
- https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
- Repositorio
.jpg)
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/218482
Ver los metadatos del registro completo
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Bi-allelic variants in NAE1 cause intellectual disability, ischiopubic hypoplasia, stress-mediated lymphopenia and neurodegenerationMuffels, Irena J. J.Schene, Imre F.Rehmann, HolgerMassink, Maarten P. G.van der Wal, Maria M.Bauder, CorinnaLabeur, MarthaArmando, Natalia GianninaLequin, Maarten H.Houben, Michiel L.Giltay, Jaques C.Haitjema, SaskiaHuisman, AlbertVansenne, FleurBluvstein, JudithPappas, JohnShailee, Lala V.Zarate, Yuri A.Mokry, Michalvan Haaften, Gijs W.Nieuwenhuis, Edward E.S.Refojo, Damianvan Wijk, FemkeFuchs, Sabine A.van Hasselt, Peter M.LYMPHOPENIANAE1NEDDYLATIONNEURODEGENERATIONOCURRENCE RATIOPHENOTYPIC SPECIFICITYPOST-TRANSLATIONAL PROTEIN MODIFICATIONPROTEASOMEUBIQUITINATIONhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Neddylation has been implicated in various cellular pathways and in the pathophysiology of numerous diseases. We identified four individuals with bi-allelic variants in NAE1, which encodes the neddylation E1 enzyme. Pathogenicity was supported by decreased NAE1 abundance and overlapping clinical and cellular phenotypes. To delineate how cellular consequences of NAE1 deficiency would lead to the clinical phenotype, we focused primarily on the rarest phenotypic features, based on the assumption that these would best reflect the pathophysiology at stake. Two of the rarest features, neuronal loss and lymphopenia worsening during infections, suggest that NAE1 is required during cellular stress caused by infections to protect against cell death. In support, we found that stressing the proteasome system with MG132—requiring upregulation of neddylation to restore proteasomal function and proteasomal stress—led to increased cell death in fibroblasts of individuals with NAE1 genetic variants. Additionally, we found decreased lymphocyte counts after CD3/CD28 stimulation and decreased NF-κB translocation in individuals with NAE1 variants. The rarest phenotypic feature—delayed closure of the ischiopubic rami—correlated with significant downregulation of RUN2X and SOX9 expression in transcriptomic data of fibroblasts. Both genes are involved in the pathophysiology of ischiopubic hypoplasia. Thus, we show that NAE1 plays a major role in (skeletal) development and cellular homeostasis during stress. Our approach suggests that a focus on rare phenotypic features is able to provide significant pathophysiological insights in diseases caused by mutations in genes with pleiotropic effects.Fil: Muffels, Irena J. J.. Utrecht University; Países BajosFil: Schene, Imre F.. Utrecht University; Países BajosFil: Rehmann, Holger. Flensburg University of Applied Sciences; AlemaniaFil: Massink, Maarten P. G.. Utrecht University; Países BajosFil: van der Wal, Maria M.. Utrecht University; Países BajosFil: Bauder, Corinna. Helmholtz Zentrum München; Alemania. Helmholtz Centre for Environmental Research; AlemaniaFil: Labeur, Martha. Helmholtz Centre for Environmental Research; AlemaniaFil: Armando, Natalia Giannina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; ArgentinaFil: Lequin, Maarten H.. Utrecht University; Países BajosFil: Houben, Michiel L.. Utrecht University; Países BajosFil: Giltay, Jaques C.. Utrecht University; Países BajosFil: Haitjema, Saskia. Utrecht University; Países BajosFil: Huisman, Albert. Utrecht University; Países BajosFil: Vansenne, Fleur. University of Groningen; Países BajosFil: Bluvstein, Judith. NYU School of Medicine; Estados UnidosFil: Pappas, John. NYU School of Medicine; Estados UnidosFil: Shailee, Lala V.. NYU School of Medicine; Estados UnidosFil: Zarate, Yuri A.. University of Arkansas for Medical Sciences; Estados UnidosFil: Mokry, Michal. Utrecht University; Países BajosFil: van Haaften, Gijs W.. Utrecht University; Países BajosFil: Nieuwenhuis, Edward E.S.. University College Roosevelt; Países BajosFil: Refojo, Damian. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina. Max Planck Institute of Psychiatry; AlemaniaFil: van Wijk, Femke. Utrecht University; Países BajosFil: Fuchs, Sabine A.. Utrecht University; Países BajosFil: van Hasselt, Peter M.. Utrecht University; Países BajosCell Press2023-01info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/218482Muffels, Irena J. J.; Schene, Imre F.; Rehmann, Holger; Massink, Maarten P. G.; van der Wal, Maria M.; et al.; Bi-allelic variants in NAE1 cause intellectual disability, ischiopubic hypoplasia, stress-mediated lymphopenia and neurodegeneration; Cell Press; American Journal Of Human Genetics; 110; 1; 1-2023; 146-1600002-9297CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/abs/pii/S0002929722005377?via%3Dihubinfo:eu-repo/semantics/altIdentifier/doi/10.1016/j.ajhg.2022.12.003info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:37:38Zoai:ri.conicet.gov.ar:11336/218482instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 10:37:38.94CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse |
| dc.title.none.fl_str_mv |
Bi-allelic variants in NAE1 cause intellectual disability, ischiopubic hypoplasia, stress-mediated lymphopenia and neurodegeneration |
| title |
Bi-allelic variants in NAE1 cause intellectual disability, ischiopubic hypoplasia, stress-mediated lymphopenia and neurodegeneration |
| spellingShingle |
Bi-allelic variants in NAE1 cause intellectual disability, ischiopubic hypoplasia, stress-mediated lymphopenia and neurodegeneration Muffels, Irena J. J. LYMPHOPENIA NAE1 NEDDYLATION NEURODEGENERATION OCURRENCE RATIO PHENOTYPIC SPECIFICITY POST-TRANSLATIONAL PROTEIN MODIFICATION PROTEASOME UBIQUITINATION |
| title_short |
Bi-allelic variants in NAE1 cause intellectual disability, ischiopubic hypoplasia, stress-mediated lymphopenia and neurodegeneration |
| title_full |
Bi-allelic variants in NAE1 cause intellectual disability, ischiopubic hypoplasia, stress-mediated lymphopenia and neurodegeneration |
| title_fullStr |
Bi-allelic variants in NAE1 cause intellectual disability, ischiopubic hypoplasia, stress-mediated lymphopenia and neurodegeneration |
| title_full_unstemmed |
Bi-allelic variants in NAE1 cause intellectual disability, ischiopubic hypoplasia, stress-mediated lymphopenia and neurodegeneration |
| title_sort |
Bi-allelic variants in NAE1 cause intellectual disability, ischiopubic hypoplasia, stress-mediated lymphopenia and neurodegeneration |
| dc.creator.none.fl_str_mv |
Muffels, Irena J. J. Schene, Imre F. Rehmann, Holger Massink, Maarten P. G. van der Wal, Maria M. Bauder, Corinna Labeur, Martha Armando, Natalia Giannina Lequin, Maarten H. Houben, Michiel L. Giltay, Jaques C. Haitjema, Saskia Huisman, Albert Vansenne, Fleur Bluvstein, Judith Pappas, John Shailee, Lala V. Zarate, Yuri A. Mokry, Michal van Haaften, Gijs W. Nieuwenhuis, Edward E.S. Refojo, Damian van Wijk, Femke Fuchs, Sabine A. van Hasselt, Peter M. |
| author |
Muffels, Irena J. J. |
| author_facet |
Muffels, Irena J. J. Schene, Imre F. Rehmann, Holger Massink, Maarten P. G. van der Wal, Maria M. Bauder, Corinna Labeur, Martha Armando, Natalia Giannina Lequin, Maarten H. Houben, Michiel L. Giltay, Jaques C. Haitjema, Saskia Huisman, Albert Vansenne, Fleur Bluvstein, Judith Pappas, John Shailee, Lala V. Zarate, Yuri A. Mokry, Michal van Haaften, Gijs W. Nieuwenhuis, Edward E.S. Refojo, Damian van Wijk, Femke Fuchs, Sabine A. van Hasselt, Peter M. |
| author_role |
author |
| author2 |
Schene, Imre F. Rehmann, Holger Massink, Maarten P. G. van der Wal, Maria M. Bauder, Corinna Labeur, Martha Armando, Natalia Giannina Lequin, Maarten H. Houben, Michiel L. Giltay, Jaques C. Haitjema, Saskia Huisman, Albert Vansenne, Fleur Bluvstein, Judith Pappas, John Shailee, Lala V. Zarate, Yuri A. Mokry, Michal van Haaften, Gijs W. Nieuwenhuis, Edward E.S. Refojo, Damian van Wijk, Femke Fuchs, Sabine A. van Hasselt, Peter M. |
| author2_role |
author author author author author author author author author author author author author author author author author author author author author author author author |
| dc.subject.none.fl_str_mv |
LYMPHOPENIA NAE1 NEDDYLATION NEURODEGENERATION OCURRENCE RATIO PHENOTYPIC SPECIFICITY POST-TRANSLATIONAL PROTEIN MODIFICATION PROTEASOME UBIQUITINATION |
| topic |
LYMPHOPENIA NAE1 NEDDYLATION NEURODEGENERATION OCURRENCE RATIO PHENOTYPIC SPECIFICITY POST-TRANSLATIONAL PROTEIN MODIFICATION PROTEASOME UBIQUITINATION |
| purl_subject.fl_str_mv |
https://purl.org/becyt/ford/1.6 https://purl.org/becyt/ford/1 |
| dc.description.none.fl_txt_mv |
Neddylation has been implicated in various cellular pathways and in the pathophysiology of numerous diseases. We identified four individuals with bi-allelic variants in NAE1, which encodes the neddylation E1 enzyme. Pathogenicity was supported by decreased NAE1 abundance and overlapping clinical and cellular phenotypes. To delineate how cellular consequences of NAE1 deficiency would lead to the clinical phenotype, we focused primarily on the rarest phenotypic features, based on the assumption that these would best reflect the pathophysiology at stake. Two of the rarest features, neuronal loss and lymphopenia worsening during infections, suggest that NAE1 is required during cellular stress caused by infections to protect against cell death. In support, we found that stressing the proteasome system with MG132—requiring upregulation of neddylation to restore proteasomal function and proteasomal stress—led to increased cell death in fibroblasts of individuals with NAE1 genetic variants. Additionally, we found decreased lymphocyte counts after CD3/CD28 stimulation and decreased NF-κB translocation in individuals with NAE1 variants. The rarest phenotypic feature—delayed closure of the ischiopubic rami—correlated with significant downregulation of RUN2X and SOX9 expression in transcriptomic data of fibroblasts. Both genes are involved in the pathophysiology of ischiopubic hypoplasia. Thus, we show that NAE1 plays a major role in (skeletal) development and cellular homeostasis during stress. Our approach suggests that a focus on rare phenotypic features is able to provide significant pathophysiological insights in diseases caused by mutations in genes with pleiotropic effects. Fil: Muffels, Irena J. J.. Utrecht University; Países Bajos Fil: Schene, Imre F.. Utrecht University; Países Bajos Fil: Rehmann, Holger. Flensburg University of Applied Sciences; Alemania Fil: Massink, Maarten P. G.. Utrecht University; Países Bajos Fil: van der Wal, Maria M.. Utrecht University; Países Bajos Fil: Bauder, Corinna. Helmholtz Zentrum München; Alemania. Helmholtz Centre for Environmental Research; Alemania Fil: Labeur, Martha. Helmholtz Centre for Environmental Research; Alemania Fil: Armando, Natalia Giannina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina Fil: Lequin, Maarten H.. Utrecht University; Países Bajos Fil: Houben, Michiel L.. Utrecht University; Países Bajos Fil: Giltay, Jaques C.. Utrecht University; Países Bajos Fil: Haitjema, Saskia. Utrecht University; Países Bajos Fil: Huisman, Albert. Utrecht University; Países Bajos Fil: Vansenne, Fleur. University of Groningen; Países Bajos Fil: Bluvstein, Judith. NYU School of Medicine; Estados Unidos Fil: Pappas, John. NYU School of Medicine; Estados Unidos Fil: Shailee, Lala V.. NYU School of Medicine; Estados Unidos Fil: Zarate, Yuri A.. University of Arkansas for Medical Sciences; Estados Unidos Fil: Mokry, Michal. Utrecht University; Países Bajos Fil: van Haaften, Gijs W.. Utrecht University; Países Bajos Fil: Nieuwenhuis, Edward E.S.. University College Roosevelt; Países Bajos Fil: Refojo, Damian. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina. Max Planck Institute of Psychiatry; Alemania Fil: van Wijk, Femke. Utrecht University; Países Bajos Fil: Fuchs, Sabine A.. Utrecht University; Países Bajos Fil: van Hasselt, Peter M.. Utrecht University; Países Bajos |
| description |
Neddylation has been implicated in various cellular pathways and in the pathophysiology of numerous diseases. We identified four individuals with bi-allelic variants in NAE1, which encodes the neddylation E1 enzyme. Pathogenicity was supported by decreased NAE1 abundance and overlapping clinical and cellular phenotypes. To delineate how cellular consequences of NAE1 deficiency would lead to the clinical phenotype, we focused primarily on the rarest phenotypic features, based on the assumption that these would best reflect the pathophysiology at stake. Two of the rarest features, neuronal loss and lymphopenia worsening during infections, suggest that NAE1 is required during cellular stress caused by infections to protect against cell death. In support, we found that stressing the proteasome system with MG132—requiring upregulation of neddylation to restore proteasomal function and proteasomal stress—led to increased cell death in fibroblasts of individuals with NAE1 genetic variants. Additionally, we found decreased lymphocyte counts after CD3/CD28 stimulation and decreased NF-κB translocation in individuals with NAE1 variants. The rarest phenotypic feature—delayed closure of the ischiopubic rami—correlated with significant downregulation of RUN2X and SOX9 expression in transcriptomic data of fibroblasts. Both genes are involved in the pathophysiology of ischiopubic hypoplasia. Thus, we show that NAE1 plays a major role in (skeletal) development and cellular homeostasis during stress. Our approach suggests that a focus on rare phenotypic features is able to provide significant pathophysiological insights in diseases caused by mutations in genes with pleiotropic effects. |
| publishDate |
2023 |
| dc.date.none.fl_str_mv |
2023-01 |
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info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion http://purl.org/coar/resource_type/c_6501 info:ar-repo/semantics/articulo |
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article |
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publishedVersion |
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http://hdl.handle.net/11336/218482 Muffels, Irena J. J.; Schene, Imre F.; Rehmann, Holger; Massink, Maarten P. G.; van der Wal, Maria M.; et al.; Bi-allelic variants in NAE1 cause intellectual disability, ischiopubic hypoplasia, stress-mediated lymphopenia and neurodegeneration; Cell Press; American Journal Of Human Genetics; 110; 1; 1-2023; 146-160 0002-9297 CONICET Digital CONICET |
| url |
http://hdl.handle.net/11336/218482 |
| identifier_str_mv |
Muffels, Irena J. J.; Schene, Imre F.; Rehmann, Holger; Massink, Maarten P. G.; van der Wal, Maria M.; et al.; Bi-allelic variants in NAE1 cause intellectual disability, ischiopubic hypoplasia, stress-mediated lymphopenia and neurodegeneration; Cell Press; American Journal Of Human Genetics; 110; 1; 1-2023; 146-160 0002-9297 CONICET Digital CONICET |
| dc.language.none.fl_str_mv |
eng |
| language |
eng |
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info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/abs/pii/S0002929722005377?via%3Dihub info:eu-repo/semantics/altIdentifier/doi/10.1016/j.ajhg.2022.12.003 |
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openAccess |
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Cell Press |
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Cell Press |
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