Since infancy and often for life, some families struggle with brittle hair due to a genetic hair loss condition called monilethrix. Researchers from the University Hospital Bonn and the University of Bonn have now discovered mutations in a keratin gene known as KRT31. They aim for this finding to enhance diagnosis for this uncommon condition. Their findings are featured in the British Journal of Dermatology.
Monilethrix is a rare inherited type of hair loss, also referred to as alopecia, that typically starts in the early months of life. It predominantly impacts the area at the back of the head. What is particularly notable is the wide range of hair loss severity, which can vary from minor thinning to total balding even among family members. The hair affected by this condition often appears as “spindle hair,” characterized by alternating knots of normal thickness, resembling a strand of pearls. The narrow sections in between are prone to break easily. In cases of dominantly inherited monilethrix, mutations in three keratin genes—KRT81, KRT83, and KRT86—have been found to disrupt the keratin framework, which is crucial for hair structure.
Nonsense (stop) mutation linked to “spindle hair”
The research group led by Prof. Regina Betz from the Institute of Human Genetics at the UKB, part 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 where no mutations were identified in the known genes. Consequently, they performed exome sequencing on six affected family members, analyzing all protein-coding areas in their genetic material.
The Bonn researchers discovered a nonsense (stop) mutation in the KRT31 gene in all six affected individuals, leading to premature cessation in protein synthesis. By conducting further sequencing, they also identified this mutation in other affected relatives. Prof. Betz’s group was able to classify KRT31 as a new gene associated with monilethrix. “Although the affected families in Germany do not know each other and are from different areas, we found that this mutation likely originated from a shared ancestor and has been inherited through many generations. It will be interesting to determine whether this mutation exists elsewhere in Europe or globally, but it seems probable,” mentioned Xing Xiong, a doctoral student at the University of Bonn’s Institute of Human Genetics at the UKB.
Gene position within the cell influences its function
The researchers examined the role of KRT31 more closely. The protein produced by KRT31, like many keratins, plays a part in developing skin cells. These proteins group together to form fibrous structures that serve as cell support. Defects in these proteins can lead to skin and hair disorders. Microscope examinations using immunofluorescence revealed that normal KRT31 is located in the cytoplasm, while the mutated version is found mostly near the cell membrane. “Thus, the mutation alters the protein’s location within the cell, which in turn compromises its function,” explained Prof. Betz.
In collaboration with the Cluster of Excellence ImmunoSensitation2 at the University of Bonn, directed by Prof. Matthias Geyer, who also leads the Institute of Structural Biology at the UKB, Prof. Betz’s group analyzed the protein’s structure and the potential impacts of the stop mutation. Typically, two keratin molecules pair up as heterodimers, aligning their ends with those of other heterodimers through the formation of disulfide bonds. “We suspect that this disulfide bond cannot be established due to the stop mutation, which may compromise the protein’s function,” Prof. Betz speculated. She firmly believes that integrating KRT31 into diagnostic panels for hair, skin, and nail conditions will enhance the diagnostics for individuals facing hair loss.
