Cystatin M/E Variant Causes Autosomal Dominant Keratosis Follicularis Spinulosa Decalvans by Dysregulating Cathepsins L and V

The study identified a pathogenic variant in the CST6 gene, encoding cystatin M/E, in a female patient with keratosis follicularis spinulosa decalvans (KFSD) and her son, indicating an autosomal dominant inheritance pattern. This variant caused dysregulation of cathepsins L and V, which are crucial for epidermal barrier function and keratinocyte differentiation. Patient cells showed increased expression of CTSL and CTSV and reduced expression of TGM1 and TGM3, leading to disrupted transglutaminase activation, essential for hair shaft development and epidermal differentiation. The study emphasized the role of cystatin M/E in KFSD and suggested further research to explore the effects of the CST6 variant on cathepsin expression and activity.