Related Experiment Video
Updated: Aug 11, 2025
Observing Mitotic Division and Dynamics in a Live Zebrafish Embryo
Published on: July 15, 2016
SMPD4 regulates mitotic nuclear envelope dynamics and its loss causes microcephaly and diabetes
Daphne J Smits1, Rachel Schot1, Nathalie Krusy2
1Department of Clinical Genetics, ErasmusMC University Medical Center Rotterdam, Rotterdam 3015GD, The Netherlands.
Abstract:
Biallelic loss-of-function variants in SMPD4 cause a rare and severe neurodevelopmental disorder with progressive congenital microcephaly and early death. SMPD4 encodes a sphingomyelinase that hydrolyses 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 and interacts with nuclear pore complexes (NPC). We refine the clinical phenotype of loss-of-function 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 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 nuclear envelope 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 nuclear envelope. 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, nuclear envelope 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.
Insights
Loss-of-function variants in SMPD4 cause a severe neurodevelopmental disorder and microcephaly. Affected individuals also develop insulin-dependent diabetes, linked to impaired nuclear envelope function and NPC insertion.
Area of Science:
- Genetics and Molecular Biology
- Neuroscience
- Endocrinology
Background:
- Biallelic loss-of-function variants in SMPD4 lead to a severe neurodevelopmental disorder characterized by microcephaly and early mortality.
- SMPD4 encodes a neutral sphingomyelinase crucial for sphingomyelin hydrolysis and membrane lipid homeostasis, localizing to the endoplasmic reticulum and nuclear envelope, and interacting with nuclear pore complexes (NPCs).
Purpose of the Study:
- To refine the clinical phenotype of SMPD4 loss-of-function variants, including age-dependent non-cerebral abnormalities.
- To investigate the cellular and organ-level functions of SMPD4, particularly its role in neural development and pancreatic beta-cell function.
Main Methods:
- Clinical characterization of five individuals from three families with SMPD4 variants, including longitudinal data.
- In vitro studies using human neural stem cells and fibroblasts to assess SMPD4 function, including knock-down experiments.
- In vivo studies using embryonic mouse brain models to evaluate the impact of Smpd4 knockdown on cortical development.
Main Results:
- Individuals with SMPD4 variants exhibit severe neurodevelopmental disorder, microcephaly, and insulin-dependent diabetes mellitus.
- SMPD4 depletion in neural stem cells reduces proliferation, prolongs mitosis, and impairs nuclear envelope reassembly and NPC insertion.
- SMPD4 deficiency in fibroblasts shows reduced neutral sphingomyelinase activity without altering bulk lipid levels, suggesting a localized function.
- Smpd4 knockdown in mouse embryos disrupts cortical progenitor proliferation and promotes premature differentiation.
Conclusions:
- SMPD4 loss-of-function causes a complex disorder affecting both neurodevelopment and endocrine function, with diabetes being a frequent age-dependent manifestation.
- Impaired nuclear envelope bending and NPC insertion due to SMPD4 deficiency likely underlie the observed cerebral corticogenesis defects and pancreatic beta-cell dysfunction.
- SMPD4 plays a critical role in maintaining nuclear envelope integrity during mitosis, impacting cell proliferation and differentiation in the developing brain.
Related Concept Videos
02:23Abnormal Proliferation
02:17Separation of Sister Chromatids
At the onset of anaphase, separase, a proteolytic enzyme, is...
01:23Negative Regulator Molecules
02:19The Spindle Assembly Checkpoint
Many proteins function together to control the spindle assembly checkpoint. Mutations affecting these proteins may allow cells to proceed into anaphase prematurely, resulting in the...
02:30Genomic Imprinting and Inheritance
The expression of some genes depends on which parent passed the gene to the offspring, through a phenomenon known as...
02:15M-Cdk Drives Transition Into Mitosis
Cyclin-dependent kinases, or Cdks, work in concert with cyclins to control cell cycle transitions. M-Cdk, a complex of Cdk1 bound to M cyclin, is a well-known example of this coordinated control that drives the transition from the G2 to the M phase.
M cyclin...