Homozygous Variant Causes Pure Hair and Nail Ectodermal Dysplasia via Reduction in Protein Stability.

Pure hair and nail ectodermal dysplasia (PHNED) is a congenital disorder characterized by reduced or absent hair and dystrophic nails. PHNED is caused by pathogenic variants in genes involved in hair and nail development, including . Previously reported biallelic pathogenic variants led to PHNED by either disrupting protein expression through nonsense-mediated decay or altering the DNA-binding affinity of the homeobox domain of HOXC13. Here, we report a case of -related PHNED with a rare homozygous variant, c.931C>T, p.Arg311Trp. Similarly to previously reported missense variants, p.Arg311Trp resides in the homeobox domain of HOXC13 and was assumed to lead to the decreased transcriptional activity of target genes. However, in contrast with previously reported variants, overexpression assays revealed that the p.Arg311Trp variant decreases HOXC13 protein stability, which is corroborated by a series of predictions. Computational models further suggest that p.Arg311Trp results in a structural rearrangement with loss of interhelical connection between Arg311 in -helix 3 and Glu276 in -helix 1. Altogether, our results suggest a novel molecular mechanism causative of PHNED, whereby biallelic pathogenic variants in may result in decreased protein stability and consequently decreased transcriptional activity of target genes essential for hair and nail development.