Abstract
Keratinising desquamative squamous metaplasia (KDSM) of the urinary tract is typically a sporadic condition with unclear aetiology and treatment options. It is characterised by either a focal or widespread transition of normal urothelium of the bladder and ureters to a stratified squamous keratinising epithelium. Four individuals from three generations of a single family were ascertained with a likely autosomal dominant form of syndromic KDSM. Whole genome sequencing (WGS) was performed on three affected individuals and a truncating variant (RARG NM_000966.6:c.1237C>T; NP_000957.1:p.(Arg413*)) in the gene encoding Retinoic Acid Receptor gamma (RARγ) was identified to be segregating with the phenotype. The truncating variant does not destabilise the transcript or protein produced from this allele but instead predicts the loss of half of helix 12 of RARγ, leading to reduced responsiveness of the receptor to all-trans retinoic acid via a dominant negative mechanism. Mice heterozygous for the variant demonstrated upregulation of cytokeratin-10 in the bladder and ureteric epithelium consistent with keratinising squamous metaplasia of the urothelium. The implicated dominant negative mechanism reduces retinoic acid signalling via heterodimeric receptors that incorporate the variant γ subunit and indicates that this condition may be addressable with high dose retinoic acid receptor agonists.