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

Keratosis follicularis spinulosa decalvans (KFSD) is a rare cornification disorder with an X-linked recessive inheritance in most cases. Pathogenic variants causing KFSD have been described MBTPS2 , the gene for membrane-bound zinc metalloprotease that involved cleavage of sterol regulatory element binding proteins important control transcription. Few families identified autosomal dominant KFSD. We present two members Austrian family phenotype KFSD, mother and her son. The disease was not observed parents, pointing to de novo mutation index patient. Using whole-exome sequencing, we heterozygous missense variant CST6 DNA samples from patient affected In line history, parents. codes cystatin M/E, cysteine protease inhibitor. Patient keratinocytes showed increased expression cathepsin genes CTSL CTSV reduced transglutaminase TGM1 TGM3. A relative gain active, cleaved transglutaminases found compared cells. expected affect protein targeting results marked disruption balance between M/E activity its target proteases eventually 1 3. This disturbance leads impairment terminal epidermal differentiation proper hair shaft formation seen