Bonn Researchers Identify Causative Mutations in Keratin 31 Gene for Dominant Inherited Monilethrix

New Genetic Mutation Linked to Rare Hair Loss Disorder Monilethrix

From infancy and often throughout their lives, some families suffer from a congenital form of hair loss called monilethrix, characterized by brittle, broken hair. Researchers at the University Hospital Bonn (UKB) and the University of Bonn have now identified causative mutations in another keratin gene, KRT31, offering hope for improved diagnosis of this rare condition. Their findings have been published in the prestigious British Journal of Dermatology.

Monilethrix is a rare congenital form of hair loss—medically known as alopecia—that typically begins within the first months of life. It primarily affects the occipital region of the scalp. The condition exhibits striking variability within families, ranging from mild hair thinning to complete baldness. The affected "beaded hair" derives its name from recurring nodes of normal thickness along the hair shaft, resembling a string of beads, with fragile constrictions in between that break easily. In the dominant inherited form of monilethrix, mutations in three keratin genes—KRT81, KRT83, and KRT86—have previously been linked to disruptions in the keratin network, which plays a crucial role in hair structure.

Nonsense (Stop) Mutation Linked to "Beaded Hair"

A research team led by Professor Regina Betz of the Institute of Human Genetics at UKB—a member of the Transdisciplinary Research Area (TRA) "Life & Health" and the Cluster of Excellence ImmunoSensation² at the University of Bonn—examined four families suspected of having monilethrix but lacking mutations in the three known genes. The team performed exome sequencing on six affected family members, analyzing all protein-coding regions of their genomes.

The Bonn researchers discovered that all six individuals carried a nonsense (stop) mutation in the KRT31 gene, which truncates protein synthesis prematurely. Additional sequencing confirmed this mutation in other affected family members. Thus, Betz's team identified KRT31 as a new gene associated with monilethrix. "Even though the affected families from different regions of Germany were unaware of one another, our findings suggest this mutation likely originated in a common ancestor and was passed down through many generations," says first author Xing Xiong, a doctoral student at the University of Bonn's Institute of Human Genetics at UKB. "Whether this mutation is also present across Europe or even worldwide remains to be seen, but it is probable."

Protein Localization in Cells Determines Function

The Bonn team investigated the function of KRT31 more closely. Like other keratins, the protein encoded by KRT31 contributes to the structure of skin cells. These proteins assemble into polymeric fibers, forming a cytoskeletal scaffold. Defects in these proteins can lead to skin and hair disorders. Immunofluorescence microscopy revealed that normal KRT31 localizes within the cytoplasm, whereas the mutated version accumulates primarily around the cell membrane. "The mutation alters the protein's localization within the cell, thereby impairing its function," explains Professor Betz.

In collaboration with Professor Matthias Geyer's team from the Cluster of Excellence ImmunoSensation²—Geyer serves as director of the Institute of Structural Biology at UKB—Betz's group analyzed the protein's structure and the potential effects of the stop mutation. Typically, keratin molecules pair as heterodimers, aligning end-to-end with other heterodimers via disulfide bonds. "We hypothesize that the stop mutation prevents the formation of these disulfide bonds, thereby disrupting the protein's function," says Betz. She believes that including KRT31 in diagnostic gene panels for hair, skin, and nail disorders will enhance diagnostic accuracy for individuals with hair loss.

Participating Institutions and Funding:

In addition to Bonn University Hospital (UKB) and the University of Bonn, the study involved the Cologne Center for Genomics at the University of Cologne, the Erfurt Human Genetics Practice, the Department of Dermatology at University Hospital Münster, and the Department of Dermatology, Venereology, and Allergology at University Hospital Würzburg. The research was funded by a grant from the German Research Foundation (DFG) under Germany's Excellence Strategy (EXC2151 – 390873048).

Publication: Xing Xiong et al.: A nonsense variant in KRT31 is associated with autosomal-dominant monilethrix; British Journal of Dermatology; DOI: https://doi.org/10.1093/bjd/ljae298