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.
The structure of human hair can vary widely. Some people have straight hair, while other people have curly or ‘woolly’ hair. Few people have a beaded hair structure known as ‘monilethrix’. This hair structure causes hair fragility, leads to hair loss and may be associated with changes in the skin and/or nails. Monilethrix is a genetic condition, which means that it is caused by changes in an affected person’s DNA. These genetic changes are also called ‘mutations’. So far, mutations in four genes (KRT81, KRT83, KRT86 and DSG4) have been identified for monilethrix. We investigated nine people from four unrelated families who had monilethrix. In these families, we found no pathogenic variant in any of the known monilethrix genes. We then carried out a technique that allowed us to look at all their genes. We discovered a new genetic cause for monilethrix in a gene called ‘KRT31’. The protein associated with KRT31 helps to form structures termed intermediate filaments. They make up the skeleton of the cell and help maintain the integrity and mechanical properties of the hair, skin and nails. The changes we saw in KRT31 altered the protein and disrupted the location of intermediate filaments. Our study identified a new genetic cause for monilethrix. This finding expands understanding of the genes important in hair structure, skin growth and nail integrity. Our research could help improve the diagnosis and management of people with monilethrix.
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