YIF1B mutations cause a post-natal neurodevelopmental syndrome associated with Golgi and primary cilium alterations

Brain. 2020 Oct 1;143(10):2911-2928. doi: 10.1093/brain/awaa235.

Jorge Diaz ¹, Xavier Gérard ², Michel-Boris Emerit ¹, Julie Areias ¹, David Geny ¹, Julie Dégardin ³, Manuel Simonutti ³, Marie-Justine Guerquin ⁴, Thibault Collin ⁵, Cécile Viollet ¹, Jean-Marie Billard ¹, Christine Métin ⁶, Laurence Hubert ², Farzaneh Larti ⁷, Kimia Kahrizi ⁷, Rebekah Jobling ⁸, Emanuele Agolini ⁹, Ranad Shaheen ¹⁰, Alban Zigler ¹¹, Virginie Rouiller-Fabre ⁴, Jean-Michel Rozet ², Serge Picaud ³, Antonio Novelli ⁹, Seham Alameer ¹², Hossein Najmabadi ⁷, Ronald Cohn ⁸, Arnold Munnich ², Magalie Barth ¹¹, Licia Lugli ¹³, Fowzan S Alkuraya ¹⁰, Susan Blaser ¹⁴, Maha Gashlan ¹⁰, Claude Besmond ², Michèle Darmon ¹ ⁶, Justine Masson ¹ ⁶

Affiliations

1 INSERM UMR894, Center for Psychiatry and Neuroscience, Paris F-75014, Université Paris Descartes, Sorbonne Paris Cité - Paris 5, France.
2 INSERM UMR-S1163 Imagine Institute for Genetic Diseases, Paris Descartes-Sorbonne Paris Cité University, France.
3 INSERM UMR-S968, Institut de la vision, Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, Paris F-75012, Université Pierre et Marie Curie, France.
4 CEA, DSV, IRCM, SCSR, Fontenay-Aux-Roses, France.
5 Saint Pères Paris Institute for the Neurosciences CNRS - UMR 8003 Université de Paris, Paris 75006, France.
6 INSERM, UMR-S1270, Institut du Fer à Moulin, Sorbonne Université, Paris F-75005, France.
7 University of Social Welfare and Rehabilitation Sciences, Genetics Research Center, Tehran 19834, Iran.
8 The Hospital for Sick Children, Molecular Genetics, Toronto, Canada.
9 Laboratory of Medical Genetics, Bambino Gesù Children's Hospital, 00146 Rome, Italy.
10 King Faisal Specialist Hospital and Research Center, Developmental Genetics Unit, Riyadh 11211, Saudi Arabia.
11 CHU Angers, Génétique, France.
12 Department of Pediatrics, King Khaled National Guard Hospital, King Abdulaziz Medical City, Jeddah, Saudi Arabia.
13 Division of Neonatal Intensive Care Unit, Department of Pediatrics, University Hospital, 41125 Modena, Italy.
14 Division of Neuroradiology, The Hospital for Sick Children, University of Toronto, Toronto, Canada.

PMID: 33103737 DOI: 10.1093/brain/awaa235

Abstract

Human post-natal neurodevelopmental delay is often associated with cerebral alterations that can lead, by themselves or associated with peripheral deficits, to premature death. Here, we report the clinical features of 10 patients from six independent families with mutations in the autosomal YIF1B gene encoding a ubiquitous protein involved in anterograde traffic from the endoplasmic reticulum to the cell membrane, and in Golgi apparatus morphology. The patients displayed global developmental delay, motor delay, visual deficits with brain MRI evidence of ventricle enlargement, myelination alterations and cerebellar atrophy. A similar profile was observed in the Yif1b knockout (KO) mouse model developed to identify the cellular alterations involved in the clinical defects. In the CNS, mice lacking Yif1b displayed neuronal reduction, altered myelination of the motor cortex, cerebellar atrophy, enlargement of the ventricles, and subcellular alterations of endoplasmic reticulum and Golgi apparatus compartments. Remarkably, although YIF1B was not detected in primary cilia, biallelic YIF1B mutations caused primary cilia abnormalities in skin fibroblasts from both patients and Yif1b-KO mice, and in ciliary architectural components in the Yif1b-KO brain. Consequently, our findings identify YIF1B as an essential gene in early post-natal development in human, and provide a new genetic target that should be tested in patients developing a neurodevelopmental delay during the first year of life. Thus, our work is the first description of a functional deficit linking Golgipathies and ciliopathies, diseases so far associated exclusively to mutations in genes coding for proteins expressed within the primary cilium or related ultrastructures. We therefore propose that these pathologies should be considered as belonging to a larger class of neurodevelopmental diseases depending on proteins involved in the trafficking of proteins towards specific cell membrane compartments.

Keywords

ER; Golgi; neurodevelopmental delay; primary cilium.

Name
Email *

	Sorry, but the email address you supplied was invalid.