Variant-specific changes in RAC3 function disrupt corticogenesis in neurodevelopmental phenotypes-Reference-Cited by-同舟云学术

Variant-specific changes in RAC3 function disrupt corticogenesis in neurodevelopmental phenotypes

Published:2022-07-04 Issue:9 Volume:145 Page:3308-3327
ISSN:0006-8950
Container-title:Brain
language:en
Short-container-title:

Author:

Scala Marcello¹²³^ORCID,Nishikawa Masashi³,Ito Hidenori³,Tabata Hidenori³,Khan Tayyaba⁴,Accogli Andrea¹,Davids Laura⁵,Ruiz Anna⁶,Chiurazzi Pietro⁷⁸^ORCID,Cericola Gabriella⁹,Schulte Björn¹⁰,Monaghan Kristin G¹¹,Begtrup Amber¹¹,Torella Annalaura¹²¹³,Pinelli Michele¹²,Denommé-Pichon Anne Sophie¹⁴¹⁵¹⁶^ORCID,Vitobello Antonio¹⁴¹⁵^ORCID,Racine Caroline¹⁵¹⁶,Mancardi Maria Margherita¹⁷,Kiss Courtney¹⁸,Guerin Andrea¹⁸,Wu Wendy⁴¹⁹,Gabau Vila Elisabeth²⁰,Mak Bryan C²¹,Martinez-Agosto Julian A²¹²²²³,Gorin Michael B²¹²⁴²⁵,Duz Bugrahan²⁶,Bayram Yavuz²⁷²⁸,Carvalho Claudia M B²⁹³⁰,Vengoechea Jaime E⁵,Chitayat David³¹³²³³,Tan Tiong Yang³⁴^ORCID,Callewaert Bert³⁵,Kruse Bernd⁹,Bird Lynne M³⁶³⁷,Faivre Laurence¹⁴¹⁶,Zollino Marcella⁷⁸,Biskup Saskia¹⁰³⁸,Brown Gabrielle,Butte Manish J,Dell'Angelica Esteban C,Dorrani Naghmeh,Douine Emilie D,Fogel Brent L,Gutierrez Irma,Huang Alden,Krakow Deborah,Lee Hane,Loo Sandra K,Mak Bryan C,Martin Martin G,Martínez-Agosto Julian A,McGee Elisabeth,Nelson Stanley F,Nieves-Rodriguez Shirley,Palmer Christina G S,Papp Jeanette C,Parker Neil H,Renteria Genecee,Sinsheimer Janet S,Wan Jijun,Wang Lee-kai,Perry Katherine Wesseling,Nigro Vincenzo,Brunetti-Pierri Nicola,Casari Giorgio,Cappuccio Gerarda,Torella Annalaura,Pinelli Michele,Musacchia Francesco,Mutarelli Margherita,Carrella Diego,Vitiello Giuseppina,Capra Valeria,Parenti Giancarlo,Leuzzi Vincenzo,Selicorni Angelo,Maitz Silvia,Banfi Sandro,Zollino Marcella,Montomoli Mario,Milani Donatelli,Romano Corrado,Tummolo Albina,De Brasi Daniele,Coppola Antonietta,Santoro Claudia,Peron Angela,Pantaleoni Chiara,Castello Raffaele,D’Arrigo Stefano,Striano Pasquale¹²,Nigro Vincenzo¹²¹³,Severino Mariasavina³⁹^ORCID,Capra Valeria⁴⁰,Costain Gregory⁴³²³³⁴¹^ORCID,Nagata Koh ichi³⁴²^ORCID, ,

Affiliation:

1. Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa , Genoa , Italy

2. Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto Giannina Gaslini , Genoa , Italy

3. Department of Molecular Neurobiology, Institute for Developmental Research, Aichi Developmental Disability Center , 713-8 Kamiya, Kasugai 480-0392 , Japan

4. Genetics and Genome Biology, Research Institute, The Hospital for Sick Children , Toronto, Ontario , Canada

5. Department of Human Genetics, Emory Healthcare , Atlanta, GA 30322 , USA

6. Genetics Laboratory, UDIAT-Centre Diagnòstic, Parc Taulí Hospital Universitari, Institut d'Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de , Barcelona, Sabadell , Spain

7. Dipartimento Universitario Scienze della Vita e Sanità Pubblica, Sezione di Medicina Genomica, Università Cattolica Sacro Cuore , Rome , Italy

8. Genetica Medica, Fondazione Policlinico Universitario A. Gemelli IRCCS , Rome , Italy

9. Neuropediatric Department, Helios-Klinikum Hildesheim , Hildesheim , Germany

10. Praxis für Humangenetik , Tübingen , Germany

11. GeneDx , Gaithersburg, MD , USA

12. Telethon Institute of Genetics and Medicine , Pozzuoli, Naples , Italy

13. Department of Precision Medicine, University of Campania Luigi Vanvitelli , Naples , Italy

14. INSERM UMR1231 Génétique des Anomalies du Développement, Université de Bourgogne Franche-Comté , Dijon , France

15. Laboratoire de Génétique Moléculaire, UF Innovation en diagnostic génomique des maladies rares, Plateau Technique de Biologie, CHU de Dijon Bourgogne , Dijon , France

16. Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs de l'interrégion Est, FHU TRANSLAD, Hôpital d'Enfants, CHU de Dijon Bourgogne , Dijon , France

17. Unit of Child Neuropsychiatry, Department of Medical and Surgical Neuroscience and Rehabilitation, IRCCS Istituto Giannina Gaslini , Genova , Italy

18. Division of Medical Genetics, Department of Pediatrics, Queen’s University , Kingston, ON K7L 2V7 , Canada

19. Queen’s University , Kingston, ON , Canada

20. Paediatric Unit, Parc Taulí Hospital Universitari, Institut d'Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de , Barcelona, Sabadell , Spain

21. Department of Human Genetics, David Geffen School of Medicine, University of California-Los Angeles , Los Angeles, CA , USA

22. Department of Pediatrics, David Geffen School of Medicine, University of California-Los Angeles , Los Angeles, CA , USA

23. Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California-Los Angeles , Los Angeles, CA , USA

24. Department of Ophthalmology, Jules Stein Eye Institute, David Geffen School of Medicine, UCLA , Los Angeles 90095, CA , USA

25. Brain Research Institute, UCLA , Los Angeles 90095, CA , USA

26. Haseki Training and Research Hospital , Istanbul , Turkey

27. Division of Genomic Diagnostics, Department of Pathology and Laboratory Medicine, Children’s Hospital of Philadelphia , Philadelphia, PA 19104 , USA

28. Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA 19104 , USA

29. Pacific Northwest Research Institute , Seattle, WA 98122 , USA

30. Baylor College of Medicine , Houston, TX 77030 , USA

31. The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, University of Toronto , Toronto, Ontario , Canada

32. Division of Clinical and Metabolic Genetics, Department of Paediatrics, The Hospital for Sick Children , Toronto, Ontario , Canada

33. Department of Molecular Genetics, University of Toronto , Toronto, Ontario , Canada

34. Victorian Clinical Genetics Services, Murdoch Children’s Research Institute, and Department of Paediatrics, University of Melbourne , Melbourne, VIC 3052 , Australia

35. Center for Medical Genetics, Ghent University Hospital , Gent , Belgium

36. Department of Pediatrics, University of California San Diego , San Diego, CA , USA

37. Genetics/Dysmorphology, Rady Children’s Hospital San Diego , San Diego, CA , USA

38. CeGaT GmbH , Tübingen , Germany

39. Neuroradiology Unit, IRCCS Istituto Giannina Gaslini , Genoa , Italy

40. Medical Genetics Unit, IRCCS Istituto Giannina Gaslini , Genoa , Italy

41. Department of Paediatrics, University of Toronto , Toronto, Ontario , Canada

42. Department of Neurochemistry, Nagoya University Graduate School of Medicine , 65 Tsurumai-cho, Nagoya 466-8550 , Japan

Abstract

Abstract 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.

Funder

Japan Society for the Promotion of Science

KAKENHI Grant-in-Aid for Scientific Research

Practical Research Project for Rare/Intractable Diseases from Japan Agency for Medical Research and Development

United States National Institutes of Health

Publisher

Oxford University Press (OUP)

Subject

Neurology (clinical)

Link

https://academic.oup.com/brain/advance-article-pdf/doi/10.1093/brain/awac106/44386737/awac106.pdf

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