Microcephaly with simplified gyration, epilepsy, and infantile diabetes linked to inappropriate apoptosis of neural progenitors

Autores
Poulton, Cathryn J.; Schot, Rachel; Kia, Sima Kheradmand; Jones Bernal, Marta Celina; Verheijen, Frans W.; Venselaar, Hanka; Y. de Wit, Marie Claire; Graaff, Esther de; Bertoli Avella, Aida M.; Mancini, Grazia M. S.
Año de publicación
2011
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
We describe a syndrome of primary microcephaly with simplified gyral pattern in combination with severe infantile epileptic encephalopathy and early-onset permanent diabetes in two unrelated consanguineous families with at least three affected children. Linkage analysis revealed a region on chromosome 18 with a significant LOD score of 4.3. In this area, two homozygous nonconserved missense mutations in immediate early response 3 interacting protein 1 (IER3IP1) were found in patients from both families. IER3IP1 is highly expressed in the fetal brain cortex and fetal pancreas and is thought to be involved in endoplasmic reticulum stress response. We reported one of these families previously in a paper on Wolcott-Rallison syndrome (WRS). WRS is characterized by increased apoptotic cell death as part of an uncontrolled unfolded protein response. Increased apoptosis has been shown to be a cause of microcephaly in animal models. An autopsy specimen from one patient showed increased apoptosis in the cerebral cortex and pancreas beta cells, implicating premature cell death as the pathogenetic mechanism. Both patient fibroblasts and control fibroblasts treated with siRNA specific for IER3IP1 showed an increased susceptibility to apoptotic cell death under stress conditions in comparison to controls. This directly implicates IER3IP1 in the regulation of cell survival. Identification of IER3IP1 mutations sheds light on the mechanisms of brain development and on the pathogenesis of infantile epilepsy and early-onset permanent diabetes.
Facultad de Ciencias Médicas
Materia
Ciencias Médicas
microcephaly
Epilepsy
Infantile Diabetes
Nivel de accesibilidad
acceso abierto
Condiciones de uso
http://creativecommons.org/licenses/by-nc-sa/4.0/
Repositorio
SEDICI (UNLP)
Institución
Universidad Nacional de La Plata
OAI Identificador
oai:sedici.unlp.edu.ar:10915/83943

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network_name_str SEDICI (UNLP)
spelling Microcephaly with simplified gyration, epilepsy, and infantile diabetes linked to inappropriate apoptosis of neural progenitorsPoulton, Cathryn J.Schot, RachelKia, Sima KheradmandJones Bernal, Marta CelinaVerheijen, Frans W.Venselaar, HankaY. de Wit, Marie ClaireGraaff, Esther deBertoli Avella, Aida M.Mancini, Grazia M. S.Ciencias MédicasmicrocephalyEpilepsyInfantile DiabetesWe describe a syndrome of primary microcephaly with simplified gyral pattern in combination with severe infantile epileptic encephalopathy and early-onset permanent diabetes in two unrelated consanguineous families with at least three affected children. Linkage analysis revealed a region on chromosome 18 with a significant LOD score of 4.3. In this area, two homozygous nonconserved missense mutations in immediate early response 3 interacting protein 1 (<i>IER3IP1</i>) were found in patients from both families. <i>IER3IP1</i> is highly expressed in the fetal brain cortex and fetal pancreas and is thought to be involved in endoplasmic reticulum stress response. We reported one of these families previously in a paper on Wolcott-Rallison syndrome (WRS). WRS is characterized by increased apoptotic cell death as part of an uncontrolled unfolded protein response. Increased apoptosis has been shown to be a cause of microcephaly in animal models. An autopsy specimen from one patient showed increased apoptosis in the cerebral cortex and pancreas beta cells, implicating premature cell death as the pathogenetic mechanism. Both patient fibroblasts and control fibroblasts treated with siRNA specific for <i>IER3IP1</i> showed an increased susceptibility to apoptotic cell death under stress conditions in comparison to controls. This directly implicates <i>IER3IP1</i> in the regulation of cell survival. Identification of <i>IER3IP1</i> mutations sheds light on the mechanisms of brain development and on the pathogenesis of infantile epilepsy and early-onset permanent diabetes.Facultad de Ciencias Médicas2011info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionArticulohttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdf265-276http://sedici.unlp.edu.ar/handle/10915/83943enginfo:eu-repo/semantics/altIdentifier/issn/0002-9297info:eu-repo/semantics/altIdentifier/doi/10.1016/j.ajhg.2011.07.006info:eu-repo/semantics/openAccesshttp://creativecommons.org/licenses/by-nc-sa/4.0/Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0)reponame:SEDICI (UNLP)instname:Universidad Nacional de La Platainstacron:UNLP2025-09-29T11:16:06Zoai:sedici.unlp.edu.ar:10915/83943Institucionalhttp://sedici.unlp.edu.ar/Universidad públicaNo correspondehttp://sedici.unlp.edu.ar/oai/snrdalira@sedici.unlp.edu.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:13292025-09-29 11:16:06.469SEDICI (UNLP) - Universidad Nacional de La Platafalse
dc.title.none.fl_str_mv Microcephaly with simplified gyration, epilepsy, and infantile diabetes linked to inappropriate apoptosis of neural progenitors
title Microcephaly with simplified gyration, epilepsy, and infantile diabetes linked to inappropriate apoptosis of neural progenitors
spellingShingle Microcephaly with simplified gyration, epilepsy, and infantile diabetes linked to inappropriate apoptosis of neural progenitors
Poulton, Cathryn J.
Ciencias Médicas
microcephaly
Epilepsy
Infantile Diabetes
title_short Microcephaly with simplified gyration, epilepsy, and infantile diabetes linked to inappropriate apoptosis of neural progenitors
title_full Microcephaly with simplified gyration, epilepsy, and infantile diabetes linked to inappropriate apoptosis of neural progenitors
title_fullStr Microcephaly with simplified gyration, epilepsy, and infantile diabetes linked to inappropriate apoptosis of neural progenitors
title_full_unstemmed Microcephaly with simplified gyration, epilepsy, and infantile diabetes linked to inappropriate apoptosis of neural progenitors
title_sort Microcephaly with simplified gyration, epilepsy, and infantile diabetes linked to inappropriate apoptosis of neural progenitors
dc.creator.none.fl_str_mv Poulton, Cathryn J.
Schot, Rachel
Kia, Sima Kheradmand
Jones Bernal, Marta Celina
Verheijen, Frans W.
Venselaar, Hanka
Y. de Wit, Marie Claire
Graaff, Esther de
Bertoli Avella, Aida M.
Mancini, Grazia M. S.
author Poulton, Cathryn J.
author_facet Poulton, Cathryn J.
Schot, Rachel
Kia, Sima Kheradmand
Jones Bernal, Marta Celina
Verheijen, Frans W.
Venselaar, Hanka
Y. de Wit, Marie Claire
Graaff, Esther de
Bertoli Avella, Aida M.
Mancini, Grazia M. S.
author_role author
author2 Schot, Rachel
Kia, Sima Kheradmand
Jones Bernal, Marta Celina
Verheijen, Frans W.
Venselaar, Hanka
Y. de Wit, Marie Claire
Graaff, Esther de
Bertoli Avella, Aida M.
Mancini, Grazia M. S.
author2_role author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Ciencias Médicas
microcephaly
Epilepsy
Infantile Diabetes
topic Ciencias Médicas
microcephaly
Epilepsy
Infantile Diabetes
dc.description.none.fl_txt_mv We describe a syndrome of primary microcephaly with simplified gyral pattern in combination with severe infantile epileptic encephalopathy and early-onset permanent diabetes in two unrelated consanguineous families with at least three affected children. Linkage analysis revealed a region on chromosome 18 with a significant LOD score of 4.3. In this area, two homozygous nonconserved missense mutations in immediate early response 3 interacting protein 1 (<i>IER3IP1</i>) were found in patients from both families. <i>IER3IP1</i> is highly expressed in the fetal brain cortex and fetal pancreas and is thought to be involved in endoplasmic reticulum stress response. We reported one of these families previously in a paper on Wolcott-Rallison syndrome (WRS). WRS is characterized by increased apoptotic cell death as part of an uncontrolled unfolded protein response. Increased apoptosis has been shown to be a cause of microcephaly in animal models. An autopsy specimen from one patient showed increased apoptosis in the cerebral cortex and pancreas beta cells, implicating premature cell death as the pathogenetic mechanism. Both patient fibroblasts and control fibroblasts treated with siRNA specific for <i>IER3IP1</i> showed an increased susceptibility to apoptotic cell death under stress conditions in comparison to controls. This directly implicates <i>IER3IP1</i> in the regulation of cell survival. Identification of <i>IER3IP1</i> mutations sheds light on the mechanisms of brain development and on the pathogenesis of infantile epilepsy and early-onset permanent diabetes.
Facultad de Ciencias Médicas
description We describe a syndrome of primary microcephaly with simplified gyral pattern in combination with severe infantile epileptic encephalopathy and early-onset permanent diabetes in two unrelated consanguineous families with at least three affected children. Linkage analysis revealed a region on chromosome 18 with a significant LOD score of 4.3. In this area, two homozygous nonconserved missense mutations in immediate early response 3 interacting protein 1 (<i>IER3IP1</i>) were found in patients from both families. <i>IER3IP1</i> is highly expressed in the fetal brain cortex and fetal pancreas and is thought to be involved in endoplasmic reticulum stress response. We reported one of these families previously in a paper on Wolcott-Rallison syndrome (WRS). WRS is characterized by increased apoptotic cell death as part of an uncontrolled unfolded protein response. Increased apoptosis has been shown to be a cause of microcephaly in animal models. An autopsy specimen from one patient showed increased apoptosis in the cerebral cortex and pancreas beta cells, implicating premature cell death as the pathogenetic mechanism. Both patient fibroblasts and control fibroblasts treated with siRNA specific for <i>IER3IP1</i> showed an increased susceptibility to apoptotic cell death under stress conditions in comparison to controls. This directly implicates <i>IER3IP1</i> in the regulation of cell survival. Identification of <i>IER3IP1</i> mutations sheds light on the mechanisms of brain development and on the pathogenesis of infantile epilepsy and early-onset permanent diabetes.
publishDate 2011
dc.date.none.fl_str_mv 2011
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
Articulo
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://sedici.unlp.edu.ar/handle/10915/83943
url http://sedici.unlp.edu.ar/handle/10915/83943
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/issn/0002-9297
info:eu-repo/semantics/altIdentifier/doi/10.1016/j.ajhg.2011.07.006
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
http://creativecommons.org/licenses/by-nc-sa/4.0/
Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0)
eu_rights_str_mv openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by-nc-sa/4.0/
Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0)
dc.format.none.fl_str_mv application/pdf
265-276
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instname:Universidad Nacional de La Plata
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institution UNLP
repository.name.fl_str_mv SEDICI (UNLP) - Universidad Nacional de La Plata
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