Impaired retinoic acid receptor-γ signaling underlies a heritable form of urothelial keratinizing squamous metaplasia.

Keratinizing desquamative squamous metaplasia (KDSM) of the urinary tract is typically a sporadic condition with unclear etiology and treatment options. It is characterized by either a focal or widespread transition of normal urothelium of the bladder and ureters to a stratified squamous keratinizing epithelium. Four individuals from three generations of a single family were ascertained with a likely autosomal dominant form of syndromic KDSM. Whole-genome sequencing 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 destabilize 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 keratinizing squamous metaplasia of the urothelium. The implicated dominant-negative mechanism reduces retinoic acid signaling via heterodimeric receptors that incorporate the variant γ subunit and indicates that this condition may be addressable with high-dose retinoic acid receptor agonists.