Cargando…
Variant-specific changes in RAC3 function disrupt corticogenesis in neurodevelopmental phenotypes
Variants in RAC3, encoding a small GTPase RAC3 which is critical for the regulation of actin cytoskeleton and intracellular signal transduction, are associated with a rare neurodevelopmental disorder with structural brain anomalies and facial dysmorphism. We investigated a cohort of 10 unrelated par...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9473360/ https://www.ncbi.nlm.nih.gov/pubmed/35851598 http://dx.doi.org/10.1093/brain/awac106 |
_version_ | 1784789483474911232 |
---|---|
author | Scala, Marcello Nishikawa, Masashi Ito, Hidenori Tabata, Hidenori Khan, Tayyaba Accogli, Andrea Davids, Laura Ruiz, Anna Chiurazzi, Pietro Cericola, Gabriella Schulte, Björn Monaghan, Kristin G Begtrup, Amber Torella, Annalaura Pinelli, Michele Denommé-Pichon, Anne Sophie Vitobello, Antonio Racine, Caroline Mancardi, Maria Margherita Kiss, Courtney Guerin, Andrea Wu, Wendy Gabau Vila, Elisabeth Mak, Bryan C Martinez-Agosto, Julian A Gorin, Michael B Duz, Bugrahan Bayram, Yavuz Carvalho, Claudia M B Vengoechea, Jaime E Chitayat, David Tan, Tiong Yang Callewaert, Bert Kruse, Bernd Bird, Lynne M Faivre, Laurence Zollino, Marcella Biskup, Saskia Striano, Pasquale Nigro, Vincenzo Severino, Mariasavina Capra, Valeria Costain, Gregory Nagata, Koh ichi |
author_facet | Scala, Marcello Nishikawa, Masashi Ito, Hidenori Tabata, Hidenori Khan, Tayyaba Accogli, Andrea Davids, Laura Ruiz, Anna Chiurazzi, Pietro Cericola, Gabriella Schulte, Björn Monaghan, Kristin G Begtrup, Amber Torella, Annalaura Pinelli, Michele Denommé-Pichon, Anne Sophie Vitobello, Antonio Racine, Caroline Mancardi, Maria Margherita Kiss, Courtney Guerin, Andrea Wu, Wendy Gabau Vila, Elisabeth Mak, Bryan C Martinez-Agosto, Julian A Gorin, Michael B Duz, Bugrahan Bayram, Yavuz Carvalho, Claudia M B Vengoechea, Jaime E Chitayat, David Tan, Tiong Yang Callewaert, Bert Kruse, Bernd Bird, Lynne M Faivre, Laurence Zollino, Marcella Biskup, Saskia Striano, Pasquale Nigro, Vincenzo Severino, Mariasavina Capra, Valeria Costain, Gregory Nagata, Koh ichi |
author_sort | Scala, Marcello |
collection | PubMed |
description | Variants in RAC3, encoding a small GTPase RAC3 which is critical for the regulation of actin cytoskeleton and intracellular signal transduction, are associated with a rare neurodevelopmental disorder with structural brain anomalies and facial dysmorphism. We investigated a cohort of 10 unrelated participants presenting with global psychomotor delay, hypotonia, behavioural disturbances, stereotyped movements, dysmorphic features, seizures and musculoskeletal abnormalities. MRI of brain revealed a complex pattern of variable brain malformations, including callosal abnormalities, white matter thinning, grey matter heterotopia, polymicrogyria/dysgyria, brainstem anomalies and cerebellar dysplasia. These patients harboured eight distinct de novo RAC3 variants, including six novel variants (NM_005052.3): c.34G > C p.G12R, c.179G > A p.G60D, c.186_188delGGA p.E62del, c.187G > A p.D63N, c.191A > G p.Y64C and c.348G > C p.K116N. We then examined the pathophysiological significance of these novel and previously reported pathogenic variants p.P29L, p.P34R, p.A59G, p.Q61L and p.E62K. In vitro analyses revealed that all tested RAC3 variants were biochemically and biologically active to variable extent, and exhibited a spectrum of different affinities to downstream effectors including p21-activated kinase 1. We then focused on the four variants p.Q61L, p.E62del, p.D63N and p.Y64C in the Switch II region, which is essential for the biochemical activity of small GTPases and also a variation hot spot common to other Rho family genes, RAC1 and CDC42. Acute expression of the four variants in embryonic mouse brain using in utero electroporation caused defects in cortical neuron morphology and migration ending up with cluster formation during corticogenesis. Notably, defective migration by p.E62del, p.D63N and p.Y64C were rescued by a dominant negative version of p21-activated kinase 1. Our results indicate that RAC3 variants result in morphological and functional defects in cortical neurons during brain development through variant-specific mechanisms, eventually leading to heterogeneous neurodevelopmental phenotypes. |
format | Online Article Text |
id | pubmed-9473360 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-94733602022-09-15 Variant-specific changes in RAC3 function disrupt corticogenesis in neurodevelopmental phenotypes Scala, Marcello Nishikawa, Masashi Ito, Hidenori Tabata, Hidenori Khan, Tayyaba Accogli, Andrea Davids, Laura Ruiz, Anna Chiurazzi, Pietro Cericola, Gabriella Schulte, Björn Monaghan, Kristin G Begtrup, Amber Torella, Annalaura Pinelli, Michele Denommé-Pichon, Anne Sophie Vitobello, Antonio Racine, Caroline Mancardi, Maria Margherita Kiss, Courtney Guerin, Andrea Wu, Wendy Gabau Vila, Elisabeth Mak, Bryan C Martinez-Agosto, Julian A Gorin, Michael B Duz, Bugrahan Bayram, Yavuz Carvalho, Claudia M B Vengoechea, Jaime E Chitayat, David Tan, Tiong Yang Callewaert, Bert Kruse, Bernd Bird, Lynne M Faivre, Laurence Zollino, Marcella Biskup, Saskia Striano, Pasquale Nigro, Vincenzo Severino, Mariasavina Capra, Valeria Costain, Gregory Nagata, Koh ichi Brain Original Article Variants in RAC3, encoding a small GTPase RAC3 which is critical for the regulation of actin cytoskeleton and intracellular signal transduction, are associated with a rare neurodevelopmental disorder with structural brain anomalies and facial dysmorphism. We investigated a cohort of 10 unrelated participants presenting with global psychomotor delay, hypotonia, behavioural disturbances, stereotyped movements, dysmorphic features, seizures and musculoskeletal abnormalities. MRI of brain revealed a complex pattern of variable brain malformations, including callosal abnormalities, white matter thinning, grey matter heterotopia, polymicrogyria/dysgyria, brainstem anomalies and cerebellar dysplasia. These patients harboured eight distinct de novo RAC3 variants, including six novel variants (NM_005052.3): c.34G > C p.G12R, c.179G > A p.G60D, c.186_188delGGA p.E62del, c.187G > A p.D63N, c.191A > G p.Y64C and c.348G > C p.K116N. We then examined the pathophysiological significance of these novel and previously reported pathogenic variants p.P29L, p.P34R, p.A59G, p.Q61L and p.E62K. In vitro analyses revealed that all tested RAC3 variants were biochemically and biologically active to variable extent, and exhibited a spectrum of different affinities to downstream effectors including p21-activated kinase 1. We then focused on the four variants p.Q61L, p.E62del, p.D63N and p.Y64C in the Switch II region, which is essential for the biochemical activity of small GTPases and also a variation hot spot common to other Rho family genes, RAC1 and CDC42. Acute expression of the four variants in embryonic mouse brain using in utero electroporation caused defects in cortical neuron morphology and migration ending up with cluster formation during corticogenesis. Notably, defective migration by p.E62del, p.D63N and p.Y64C were rescued by a dominant negative version of p21-activated kinase 1. Our results indicate that RAC3 variants result in morphological and functional defects in cortical neurons during brain development through variant-specific mechanisms, eventually leading to heterogeneous neurodevelopmental phenotypes. Oxford University Press 2022-07-04 /pmc/articles/PMC9473360/ /pubmed/35851598 http://dx.doi.org/10.1093/brain/awac106 Text en © The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Article Scala, Marcello Nishikawa, Masashi Ito, Hidenori Tabata, Hidenori Khan, Tayyaba Accogli, Andrea Davids, Laura Ruiz, Anna Chiurazzi, Pietro Cericola, Gabriella Schulte, Björn Monaghan, Kristin G Begtrup, Amber Torella, Annalaura Pinelli, Michele Denommé-Pichon, Anne Sophie Vitobello, Antonio Racine, Caroline Mancardi, Maria Margherita Kiss, Courtney Guerin, Andrea Wu, Wendy Gabau Vila, Elisabeth Mak, Bryan C Martinez-Agosto, Julian A Gorin, Michael B Duz, Bugrahan Bayram, Yavuz Carvalho, Claudia M B Vengoechea, Jaime E Chitayat, David Tan, Tiong Yang Callewaert, Bert Kruse, Bernd Bird, Lynne M Faivre, Laurence Zollino, Marcella Biskup, Saskia Striano, Pasquale Nigro, Vincenzo Severino, Mariasavina Capra, Valeria Costain, Gregory Nagata, Koh ichi Variant-specific changes in RAC3 function disrupt corticogenesis in neurodevelopmental phenotypes |
title | Variant-specific changes in RAC3 function disrupt corticogenesis in neurodevelopmental phenotypes |
title_full | Variant-specific changes in RAC3 function disrupt corticogenesis in neurodevelopmental phenotypes |
title_fullStr | Variant-specific changes in RAC3 function disrupt corticogenesis in neurodevelopmental phenotypes |
title_full_unstemmed | Variant-specific changes in RAC3 function disrupt corticogenesis in neurodevelopmental phenotypes |
title_short | Variant-specific changes in RAC3 function disrupt corticogenesis in neurodevelopmental phenotypes |
title_sort | variant-specific changes in rac3 function disrupt corticogenesis in neurodevelopmental phenotypes |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9473360/ https://www.ncbi.nlm.nih.gov/pubmed/35851598 http://dx.doi.org/10.1093/brain/awac106 |
work_keys_str_mv | AT scalamarcello variantspecificchangesinrac3functiondisruptcorticogenesisinneurodevelopmentalphenotypes AT nishikawamasashi variantspecificchangesinrac3functiondisruptcorticogenesisinneurodevelopmentalphenotypes AT itohidenori variantspecificchangesinrac3functiondisruptcorticogenesisinneurodevelopmentalphenotypes AT tabatahidenori variantspecificchangesinrac3functiondisruptcorticogenesisinneurodevelopmentalphenotypes AT khantayyaba variantspecificchangesinrac3functiondisruptcorticogenesisinneurodevelopmentalphenotypes AT accogliandrea variantspecificchangesinrac3functiondisruptcorticogenesisinneurodevelopmentalphenotypes AT davidslaura variantspecificchangesinrac3functiondisruptcorticogenesisinneurodevelopmentalphenotypes AT ruizanna variantspecificchangesinrac3functiondisruptcorticogenesisinneurodevelopmentalphenotypes AT chiurazzipietro variantspecificchangesinrac3functiondisruptcorticogenesisinneurodevelopmentalphenotypes AT cericolagabriella variantspecificchangesinrac3functiondisruptcorticogenesisinneurodevelopmentalphenotypes AT schultebjorn variantspecificchangesinrac3functiondisruptcorticogenesisinneurodevelopmentalphenotypes AT monaghankristing variantspecificchangesinrac3functiondisruptcorticogenesisinneurodevelopmentalphenotypes AT begtrupamber variantspecificchangesinrac3functiondisruptcorticogenesisinneurodevelopmentalphenotypes AT torellaannalaura variantspecificchangesinrac3functiondisruptcorticogenesisinneurodevelopmentalphenotypes AT pinellimichele variantspecificchangesinrac3functiondisruptcorticogenesisinneurodevelopmentalphenotypes AT denommepichonannesophie variantspecificchangesinrac3functiondisruptcorticogenesisinneurodevelopmentalphenotypes AT vitobelloantonio variantspecificchangesinrac3functiondisruptcorticogenesisinneurodevelopmentalphenotypes AT racinecaroline variantspecificchangesinrac3functiondisruptcorticogenesisinneurodevelopmentalphenotypes AT mancardimariamargherita variantspecificchangesinrac3functiondisruptcorticogenesisinneurodevelopmentalphenotypes AT kisscourtney variantspecificchangesinrac3functiondisruptcorticogenesisinneurodevelopmentalphenotypes AT guerinandrea variantspecificchangesinrac3functiondisruptcorticogenesisinneurodevelopmentalphenotypes AT wuwendy variantspecificchangesinrac3functiondisruptcorticogenesisinneurodevelopmentalphenotypes AT gabauvilaelisabeth variantspecificchangesinrac3functiondisruptcorticogenesisinneurodevelopmentalphenotypes AT makbryanc variantspecificchangesinrac3functiondisruptcorticogenesisinneurodevelopmentalphenotypes AT martinezagostojuliana variantspecificchangesinrac3functiondisruptcorticogenesisinneurodevelopmentalphenotypes AT gorinmichaelb variantspecificchangesinrac3functiondisruptcorticogenesisinneurodevelopmentalphenotypes AT duzbugrahan variantspecificchangesinrac3functiondisruptcorticogenesisinneurodevelopmentalphenotypes AT bayramyavuz variantspecificchangesinrac3functiondisruptcorticogenesisinneurodevelopmentalphenotypes AT carvalhoclaudiamb variantspecificchangesinrac3functiondisruptcorticogenesisinneurodevelopmentalphenotypes AT vengoecheajaimee variantspecificchangesinrac3functiondisruptcorticogenesisinneurodevelopmentalphenotypes AT chitayatdavid variantspecificchangesinrac3functiondisruptcorticogenesisinneurodevelopmentalphenotypes AT tantiongyang variantspecificchangesinrac3functiondisruptcorticogenesisinneurodevelopmentalphenotypes AT callewaertbert variantspecificchangesinrac3functiondisruptcorticogenesisinneurodevelopmentalphenotypes AT krusebernd variantspecificchangesinrac3functiondisruptcorticogenesisinneurodevelopmentalphenotypes AT birdlynnem variantspecificchangesinrac3functiondisruptcorticogenesisinneurodevelopmentalphenotypes AT faivrelaurence variantspecificchangesinrac3functiondisruptcorticogenesisinneurodevelopmentalphenotypes AT zollinomarcella variantspecificchangesinrac3functiondisruptcorticogenesisinneurodevelopmentalphenotypes AT biskupsaskia variantspecificchangesinrac3functiondisruptcorticogenesisinneurodevelopmentalphenotypes AT variantspecificchangesinrac3functiondisruptcorticogenesisinneurodevelopmentalphenotypes AT variantspecificchangesinrac3functiondisruptcorticogenesisinneurodevelopmentalphenotypes AT strianopasquale variantspecificchangesinrac3functiondisruptcorticogenesisinneurodevelopmentalphenotypes AT nigrovincenzo variantspecificchangesinrac3functiondisruptcorticogenesisinneurodevelopmentalphenotypes AT severinomariasavina variantspecificchangesinrac3functiondisruptcorticogenesisinneurodevelopmentalphenotypes AT capravaleria variantspecificchangesinrac3functiondisruptcorticogenesisinneurodevelopmentalphenotypes AT costaingregory variantspecificchangesinrac3functiondisruptcorticogenesisinneurodevelopmentalphenotypes AT nagatakohichi variantspecificchangesinrac3functiondisruptcorticogenesisinneurodevelopmentalphenotypes |