William Davies PhD

Reader Cardiff University Schools of Medicine and Psychology

Award: $50,000

OBJECTIVE:

To use a new mouse model to understand the biology of XLI and associated medical conditions. The proposed project has the potential to identify, for the first time, biological processes underlying conditions which have large effects on quality-of-life, morbidity and mortality in individuals affected by the second most common subtype of ichthyosis; this, in turn, may point to potential therapeutic targets in XLI which may be investigated in future work.

AIMS:

To breed and behaviourally-test adult wildtype (WT) and homozygous male mice (lacking the X-linked ichthyosis-associated protein steroid sulfatase (STS)

To compare gene expression between adult WT and homozygous male mice in three key tissues associated with XLI phenotypes: skin, brain and heart

To identify general, and tissue-specific, biological pathways perturbed in male mice lacking STS with a view to identifying novel therapeutic targets in XLI 

METHODS:

We will breed and behaviourally-test wildtype (n=12) and homozygous (n=12) adult male mice lacking funcitonal STS protein (as a consequence of a 22 nucleotide frame-shifting deletion in critical exon 2), and, post mortem collect ear skin, brain region striatal), and whole heart tissues for RNA extraction. For the brain and heart samples, we will compare global gene expression in wildtype and mutant tissues via bulk RNASeq analysis using illumina sequencing with -70million raw reads per sample according to standard protocols. Using a combination of differential gene expression analysis (DESeq2) and Gene Ontology/Pathway software (e.g. DAVID) we will identify heart/brain gene expression differences/pathways that differ between the genotypes across both tissues, or in a tissue-specific manner. Selected gene expression differences will be followed up with immunohistochemistry in additional animals (n=6 per group). Using quantitative PCR, we will test whether gene expression differences observed in heart/brain are also seen in skin samples. Using a similar Sts-deletion mouse, colleagues in South Korea have recently identified gene pathways disturbed in the skin (doi:10.1016/j.bbadis.2023.167004) and we also aim to replicate these initial findings. The proposed study will allow us to prioritise causal mechanisms underlying serious XLI-associated phenotypes.

RELEVANCE TO MISSION OF FIRST:

In collaboration with FIRST and Ichthyosis Support Group UK, our research group have shown that XLI is associated with a substantially-increased risk of Attention Deficit Hyperactivity Disorder (ADHD)(affecting 30-40% of individuals)(doi:10.1371/journal.pone.0164417) which may be due to smaller volume of basal ganglia subregions (doi: 10.1136/jmedgenet-2019-106676). We have also shown that XLI is associated with a substantially-increased risk of heart arrhythmias (affecting 30-40% of individuals))(doi:10.1136/jmedgenet-2019-106676 and 10.1136/jmg-2022-108862) which confer significantly increased risk of heart failure, stroke and accelerated cognitive decline and which could predispose to Sudden Arrhythmic Death Syndrome
(SADS)(doi:10.14744/AnatolJCardiol.2025.4903). The planned work will identify biological pathways underlying these common and disabling comorbidities within XLI, and will indicate promising novel therapeutic targets.

Researchers interested in funding Through FIRST'S Research Grant Program