# SMPD4: Role of a microcephaly gene in ceramide biosynthesis and human brain development

> **NIH NIH F31** · CINCINNATI CHILDRENS HOSP MED CTR · 2021 · $38,756

## Abstract

Brain development in mammals begins early in embryogenesis and continues after birth. Intricate
patterns of neural progenitor proliferation, differentiation, and migration are established early in
neural development and are essential for this process. Our interest lies in primary microcephaly,
a disorder of development which results primarily in a decrease in dorsal cortex size in humans.
Microcephaly is a congenital, often genetic, malformation which affects 25,000 U.S. children per
year. Currently, there are no treatments for this disorder. We recently published a cohort of twenty-
three pediatric patients from twelve unrelated families with damaging variants in the gene SMPD4
(neutral sphingomyelinase-3/nSMase3) whose primary clinical finding is microcephaly. SMPD4
hydrolyzes sphingomyelin in the cell membrane to produce phosphocholine and ceramide.
Ceramide is required for primary ciliogenesis. The objective of this proposal is to elucidate the
function of SMPD4 in the brain in order to recognize why loss of this gene causes disorder of
brain development in human patients. Our central hypothesis is that SMPD4 expression is
uniquely required for human cortical neurogenesis via regulating proper sphingolipid biosynthesis.
We propose to 1) specify the impact of loss of SMPD4 upon forebrain development, 2) determine
the cellular mechanism of SMPD4 microcephaly, and 3) investigate the role of sphingolipid
biosynthesis pathway components in this disorder. In Aim 1, I will use human pluripotent stem
cell-derived neural rosettes and a conditional genetic ablation in mice to confirm the pathogenicity
of human SMPD4 variants upon forebrain development. In Aim 2, I will define the requirement for
SMPD4 in specific neural cell types, hypothesizing that SMPD4 is required in neural progenitors
in the ventricular zone and regulates primary ciliogenesis in these cells. In Aim 3, I will assess
cellular levels of key sphingolipid molecules in control and SMPD4 loss of function models and
modulate sphingolipid pathway components using exogenous chemical treatment. I hypothesize
that loss of SMPD4 decreases the level of ceramide and its downstream products, and rescuing
ceramide biogenesis is sufficient to improve brain phenotypes. The results of the proposed work
will contribute to both our understanding of SMPD4 pathogenicity in human patients with
microcephaly and the role of the sphingolipid pathway in human brain development.

## Key facts

- **NIH application ID:** 10315128
- **Project number:** 1F31HD104350-01A1
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Katherine Inskeep
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $38,756
- **Award type:** 1
- **Project period:** 2021-09-03 → 2024-09-02

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10315128

## Citation

> US National Institutes of Health, RePORTER application 10315128, SMPD4: Role of a microcephaly gene in ceramide biosynthesis and human brain development (1F31HD104350-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10315128. Licensed CC0.

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