SMPD4

Cilia effects upon perturbation of SMPD4

Cilia number / % ciliated:

Decreased cilia number

Phenotypes

Mouse phenotype:

Smpd4 null mice: cerebellar hypoplasia, perinatal lethality (incomplete penetrance), failure to thrive, Purkinje cell loss.

Mouse ciliopathy phenotype:

Smpd4-deficient Purkinje cell cilia are longer than wild-type. Cilia phenotype more pronounced in human iPSCs than in mouse neurons, suggesting species-specific role.

Human ciliopathy phenotype:

Patient iPSCs derived from individual with NEDMABA (Family 8, Magini et al. 2019) show shortened and bulbous primary cilia rescued by exogenous ceramide (Inskeep et al. 2024).

Ciliopathy associations

• Neurodevelopmental Disorder with Microcephaly, Arthrogryposis, and Structural Brain Anomalies

Subcellular localization

cilia, endoplasmic reticulum, nuclear envelope

Functional category

• Ciliary assembly/disassembly
• Lipid metabolism
• Sphingolipid biosynthesis

Function

Neutral sphingomyelinase that metabolises sphingomyelin into ceramide at the nuclear envelope and ER. SMPD4-deficient patient iPSCs show shortened and bulbous primary cilia, rescued by exogenous ceramide treatment. Smpd4-null and forebrain-specific knockout mice exhibit cerebellar hypoplasia from Purkinje cell loss. Patient iPSC-derived neural rosettes and organoids show reduced neural progenitor cells, decreased proliferation, and increased cell death (Inskeep et al. 2024). Variants in SMPD4 cause neurodevelopmental disorder with microcephaly, arthrogryposis, and structural brain anomalies (NEDMABA), reported in 23 individuals from 12 families (Magini et al. 2019).