A nonsense variant in KRT31 is associated with autosomal dominant monilethrix.

Background: Monilethrix is a rare hereditary hair disorder that is characterized by a beaded hair shaft structure and increased hair fragility. Patients may also present with keratosis pilaris and nail changes. Research has identified three genes responsible for autosomal dominant monilethrix (KRT81, KRT83, KRT86) and one responsible for the autosomal recessive form (DSG4).

Objectives: To investigate the genetic basis of autosomal dominant monilethrix in families with no pathogenic variants in any of the known monilethrix genes, and to understand the mechanistic basis of variant pathogenicity using a cellular model.

Methods: Nine affected individuals from four unrelated families were included. A clinical diagnosis of monilethrix was assigned based on clinical examination and/or trichoscopy. Exome sequencing was performed in six individuals to identify pathogenic variants; Sanger sequencing was used for co-segregation and haplotype analyses. Cell culture experiments [immunoblotting, immunofluorescence and reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) analyses] were used to confirm variant pathogenicity, to determine the expression and subcellular localization of proteins, and to identify possible nonsense-mediated mRNA decay.

Results: In six affected individuals with clinically suggested monilethrix, exome sequencing led to the identification of the nonsense variant c.1081G>T; p.(Glu361*) in KRT31, which was subsequently identified in other affected members of these families by Sanger sequencing. This variant led to the abolition of both the last three amino acids of the 2B subdomain and the complete C-terminal tail domain of keratin 31. Immunoblotting demonstrated that when co-expressed with its binding partner keratin 85, the truncated keratin 31 was still expressed, albeit less abundantly than the wildtype protein. Immunofluorescence revealed that p.(Glu361*) keratin 31 had an altered cytoskeletal localization and formed vesicular-like structures in the cell cytoplasm near the cell membrane. RT-qPCR analysis did not generate evidence for nonsense-mediated decay of the mutant transcript.

Conclusions: This study is the first to identify pathogenic variants in KRT31 as a cause of autosomal dominant monilethrix. This highlights the importance of hair keratin proteins in hair biology, and will increase the molecular diagnostic yield for rare ectodermal phenotypes of hair and nail tissues.