# Roles of the X-linked Intellectual Disability gene ZDHHC9 in White Matter formation

> **NIH NIH R21** · TEMPLE UNIV OF THE COMMONWEALTH · 2021 · $420,200

## Abstract

Abstract:
The myelin sheaths that wrap around axons in the Central Nervous System (CNS) are damaged or formed
incorrectly in many developmental brain disorders. We thus sought to better understand the control of
myelination and how it may be impaired in such conditions. Essentially all of the major myelin proteins are
covalently modified with the lipid palmitate, a process that is often critical for correct protein subcellular
localization and function, but how myelin protein palmitoylation is controlled is unknown. We were therefore
struck by findings that the X-linked Intellectual Disability (XLID) gene ZDHHC9 codes for a specific palmitoyl
acyltransferase enzyme that is highly expressed in oligodendrocytes (OLs), the myelinating cells of the CNS.
Importantly, human patients with ZDHHC9 loss-of-function mutations and Zdhhc9 knockout (KO) mice display
cognitive deficits and have markedly reduced forebrain white matter volume, suggesting a key role for
ZDHHC9 in OL formation and/or function. Our own studies revealed that Zdhhc9 KO mice have impaired
corpus callosal myelination without loss of neuronal axons and that Zdhhc9 knockdown cell-autonomously
impairs OL maturation after differentiation from Oligodendrocyte Precursor Cells (OPCs) in culture. These
striking phenotypes may account for the intellectual disability and/or epileptic seizures seen in human patients
with ZDHHC9 mutations. In this project we will more precisely define links between Zdhhc9 mutation and
myelination impairments. In Aim 1, we will combine well-established Electron Microscopic (EM) and
immunostaining analyses with a genetic fate-mapping strategy to comprehensively define how Zdhhc9 loss
impacts OL distribution and axonal myelination in vivo. In Aim 2 we will more precisely determine how cell-
autonomous Zdhhc9 loss affects OL differentiation and morphological elaboration. In each Aim we will
compare the ability of wild type (wt) and XLID mutant forms of ZDHHC9 to rescue the observed phenotypes.
These studies will provide new insights regarding not just the impact of Zdhhc9 loss, but also palmitoylation-
dependent control of myelination, a process first reported decades ago but about which almost nothing is
known. Insights from this work could thus be invaluable to those studying a range of brain disorders marked by
White Matter Impairments.

## Key facts

- **NIH application ID:** 10354435
- **Project number:** 1R21NS125202-01
- **Recipient organization:** TEMPLE UNIV OF THE COMMONWEALTH
- **Principal Investigator:** Gareth Thomas
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $420,200
- **Award type:** 1
- **Project period:** 2021-09-20 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10354435

## Citation

> US National Institutes of Health, RePORTER application 10354435, Roles of the X-linked Intellectual Disability gene ZDHHC9 in White Matter formation (1R21NS125202-01). Retrieved via AI Analytics 2026-06-14 from https://api.ai-analytics.org/grant/nih/10354435. Licensed CC0.

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