Article (Scientific journals)
SMPD4 regulates mitotic nuclear envelope dynamics and its loss causes microcephaly and diabetes.
Smits, Daphne J; Schot, Rachel; Krusy, Nathalie et al.
2023In Brain: a Journal of Neurology
Peer Reviewed verified by ORBi
 

Files


Full Text
Brain (2023) Smits.pdf
Author postprint (2.1 MB)
Request a copy

All documents in ORBi are protected by a user license.

Send to



Details



Keywords :
SMPD4; insulin dependent diabetes; lipid homeostasis; microcephaly; nuclear envelope; Neurology (clinical)
Abstract :
[en] Biallelic loss of function (LoF) variants in SMPD4 cause a rare and severe neurodevelopmental disorder with progressive congenital microcephaly and early death. SMPD4 encodes a sphingomyelinase that hydrolyzes sphingomyelin into ceramide at neutral pH and can thereby affect membrane lipid homeostasis. SMPD4 localizes to the membranes of the endoplasmic reticulum and nuclear envelope (NE), and interacts with nuclear pore complexes (NPC). We refine the clinical phenotype of LoF SMPD4 variants by describing five individuals from three unrelated families with longitudinal data due to prolonged survival. All individuals surviving beyond infancy developed insulin-dependent diabetes, besides presenting with a severe neurodevelopmental disorder (NDD) and microcephaly, making diabetes one of the most frequent age-dependent non-cerebral abnormalities. We studied the function of SMPD4 at the cellular and organ levels. Knock-down of SMPD4 in human neural stem cells, causes reduced proliferation rates and prolonged mitosis. Moreover, SMPD4 depletion results in abnormal NE breakdown and reassembly during mitosis and decreased post-mitotic NPC insertion. Fibroblasts from affected individuals show deficient SMPD4-specific neutral sphingomyelinase activity, without changing (sub)cellular lipidome fractions, which suggests a local function of SMPD4 on the NE. In embryonic mouse brain, knockdown of Smpd4 impairs cortical progenitor proliferation and induces premature differentiation by altering the balance between neurogenic and proliferative progenitor cell divisions. We hypothesize that, in individuals with SMPD4-related disease, NE bending, which is needed to insert NPCs in the nuclear envelope, is impaired in the absence of SMPD4, and interferes with cerebral corticogenesis and survival of pancreatic beta cells.
Disciplines :
Neurology
Author, co-author :
Smits, Daphne J ;  Department of Clinical Genetics, ErasmusMC University Medical Center Rotterdam, Rotterdam, The Netherlands
Schot, Rachel;  Department of Clinical Genetics, ErasmusMC University Medical Center Rotterdam, Rotterdam, The Netherlands
Krusy, Nathalie ;  Université de Liège - ULiège > Département des sciences biomédicales et précliniques
Wiegmann, Katja;  Institute for Medical Microbiology, Immunology, and Hygiene, University Hospital Cologne, Center for Molecular Medicine Cologne, University of Cologne, 50935 Colgne, Germany
Utermöhlen, Olaf;  Institute for Medical Microbiology, Immunology, and Hygiene, University Hospital Cologne, Center for Molecular Medicine Cologne, University of Cologne, 50935 Colgne, Germany
Mulder, Monique T;  Department of Internal Medicine, ErasmusMC University Medical Center Rotterdam, Rotterdam, The Netherlands
den Hoedt, Sandra;  Department of Internal Medicine, ErasmusMC University Medical Center Rotterdam, Rotterdam, The Netherlands
Yoon, Grace;  Division of Clinical and Metabolic Genetics, Department of Paediatrics, University of Toronto, The Hospital for Sick Children, Toronto, Canada
Deshwar, Ashish R ;  Division of Clinical and Metabolic Genetics, Department of Paediatrics, University of Toronto, The Hospital for Sick Children, Toronto, Canada
Kresge, Christina;  Rutgers New Jersey Medical School, Newark, New Jersey, USA
Pletcher, Beth;  Rutgers New Jersey Medical School, Newark, New Jersey, USA
van Mook, Maura;  Department of Clinical Genetics, ErasmusMC University Medical Center Rotterdam, Rotterdam, The Netherlands
Ferreira, Marta Serio;  Department of Clinical Genetics, ErasmusMC University Medical Center Rotterdam, Rotterdam, The Netherlands
Poot, Raymond A;  Department of Cell biology, ErasmusMC University Medical Center Rotterdam, Rotterdam, The Netherlands
Slotman, Johan A;  Department of Pathology, Optical Imaging Center, ErasmusMC University Medical Center Rotterdam, Rotterdam, The Netherlands
Kremers, Gert-Jan;  Department of Pathology, Optical Imaging Center, ErasmusMC University Medical Center Rotterdam, Rotterdam, The Netherlands
Ahmad, Abeer;  Pediatric Endocrinology Unit, Department of Pediatrics, Adan Hospital, Hadiya 52700, Kuwait
Albash, Buthaina;  Kuwait Medical Genetics Centre, Ministry of Health, Sulaibikhat 80901, Kuwait
Bastaki, Laila;  Kuwait Medical Genetics Centre, Ministry of Health, Sulaibikhat 80901, Kuwait
Marafi, Dana;  Kuwait Medical Genetics Centre, Ministry of Health, Sulaibikhat 80901, Kuwait ; Section of Child Neurology, Department of Pediatrics, Adan Hospital, Hadiya 52700, Kuwait ; Department of Pediatrics, Faculty of Medicine, Kuwait University, P.O. Box 24923, Safat 13110, Kuwait
Dekker, Jordy;  Department of Clinical Genetics, ErasmusMC University Medical Center Rotterdam, Rotterdam, The Netherlands
van Ham, Tjakko J ;  Department of Clinical Genetics, ErasmusMC University Medical Center Rotterdam, Rotterdam, The Netherlands
Nguyen, Laurent  ;  Université de Liège - ULiège > Département des sciences biomédicales et précliniques
Mancini, Grazia M S ;  Department of Clinical Genetics, ErasmusMC University Medical Center Rotterdam, Rotterdam, The Netherlands
More authors (14 more) Less
Language :
English
Title :
SMPD4 regulates mitotic nuclear envelope dynamics and its loss causes microcephaly and diabetes.
Publication date :
03 February 2023
Journal title :
Brain: a Journal of Neurology
ISSN :
0006-8950
eISSN :
1460-2156
Publisher :
Oxford University Press (OUP), England
Peer reviewed :
Peer Reviewed verified by ORBi
Funders :
ZonMw - Nederlandse Organisatie voor Gezondheidsonderzoek en Zorginnovatie [NL]
Available on ORBi :
since 03 July 2023

Statistics


Number of views
30 (1 by ULiège)
Number of downloads
0 (0 by ULiège)

Scopus citations®
 
2
Scopus citations®
without self-citations
1
OpenCitations
 
0

Bibliography


Similar publications



Contact ORBi