TY - JOUR
T1 - YIF1B mutations cause a post-natal neurodevelopmental syndrome associated with Golgi and primary cilium alterations
AU - Diaz, Jorge
AU - Gérard, Xavier
AU - Emerit, Michel Boris
AU - Areias, Julie
AU - Geny, David
AU - Dégardin, Julie
AU - Simonutti, Manuel
AU - Guerquin, Marie Justine
AU - Collin, Thibault
AU - Viollet, Cécile
AU - Billard, Jean Marie
AU - Métin, Christine
AU - Hubert, Laurence
AU - Larti, Farzaneh
AU - Kahrizi, Kimia
AU - Jobling, Rebekah
AU - Agolini, Emanuele
AU - Shaheen, Ranad
AU - Zigler, Alban
AU - Rouiller-Fabre, Virginie
AU - Rozet, Jean Michel
AU - Picaud, Serge
AU - Novelli, Antonio
AU - Alameer, Seham
AU - Najmabadi, Hossein
AU - Cohn, Ronald
AU - Munnich, Arnold
AU - Barth, Magalie
AU - Lugli, Licia
AU - Alkuraya, Fowzan S.
AU - Blaser, Susan
AU - Gashlan, Maha
AU - Besmond, Claude
AU - Darmon, Michèle
AU - Masson, Justine
N1 - Publisher Copyright:
© 2020 The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.
PY - 2020/10/1
Y1 - 2020/10/1
N2 - 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.
AB - 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.
KW - ER
KW - Golgi
KW - neurodevelopmental delay
KW - primary cilium
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U2 - 10.1093/brain/awaa235
DO - 10.1093/brain/awaa235
M3 - Article
C2 - 33103737
AN - SCOPUS:85094683517
VL - 143
SP - 2911
EP - 2928
JO - Brain
JF - Brain
SN - 0006-8950
IS - 10
ER -