A Missense Mutation Within the Helix Initiation Motif of the Keratin K71 Gene Underlies Autosomal Dominant Woolly Hair/Hypotrichosis

The study on the RCO3 mouse model identified that alopecia was caused by a deficiency in the mK6irs1 gene, due to a 10-bp deletion leading to a frameshift and loss of crucial amino acids necessary for intermediate filament formation. This mutation affected the inner root sheath of hair follicles, specifically disrupting keratinization in Henle's and Huxley's layers, resulting in malformed hair shafts. The research involved 437 individuals and concluded that the absence of mK6irs1 led to structural hair defects and alopecia, emphasizing the gene's essential role in normal hair development. The findings suggested potential parallels in human hair fragility syndromes.

The study identified and characterized four inner-root-sheath-specific type II epithelial keratins, K6irs1, K6irs2, K6irs3, and K6irs4, in the human hair follicle. K6irs3 and K6irs4 were newly discovered and, along with K6irs1 and K6irs2, formed a distinct gene cluster on chromosome 12q13. These keratins were expressed in specific layers of the inner root sheath (IRS), with K6irs3 starting in the lowermost bulb region and K6irs4 restricted to the Huxley layer. The research provided insights into the structural and evolutionary relationships among IRS keratins and their roles in hair follicle compartments, enhancing the understanding of hair follicle biology and keratinization processes. Additionally, the study highlighted the role of Flügelzellen, specialized Huxley cells marked by K6irs4, in contributing to the flexibility and resilience of the hair follicle structure.

This review explored the structure, function, and regulation of keratin intermediate filaments (IFs), highlighting both established ('hard') and emerging ('soft') principles. It discussed the discovery of novel keratin genes, the mechanics of keratin filaments, and the functional redundancy revealed by gene knockouts. The study also examined the role of keratin mutations in various diseases and the regulation of keratin through interactions with other proteins. The field was noted to be rapidly advancing, driven by transgenic models and new insights into keratin's protective roles in cellular stress responses.

The study identified a novel type II cytokeratin, mK6irs, specifically expressed in the Huxley and Henle layers of the mouse inner root sheath (IRS) during the anagen phase of hair growth. This 57 kDa protein showed homology with other cytokeratins and was confirmed through various analyses to be present only during specific phases of the hair cycle. The research suggested that mK6irs played a role in the differentiation and structure of the IRS, contributing to the understanding of hair follicle biology. Additionally, the study proposed that mK6irs could be important for understanding hereditary hair diseases, as mutations in keratins are linked to conditions like cicatricial alopecia and monilethrix.