PDF(Pubmed)
Abstract：
Keratosis follicularis spinulosa decalvans (KFSD) is a rare cornification disorder with an X-linked recessive inheritance in most cases. Pathogenic variants causing X-linked KFSD have been described in MBTPS2, the gene for a membrane-bound zinc metalloprotease that is involved in the cleavage of sterol regulatory element binding proteins important for the control of transcription. Few families have been identified with an autosomal dominant inheritance of KFSD. We present two members of an Austrian family with a phenotype of KFSD, a mother and her son. The disease was not observed in her parents, pointing to a dominant inheritance with a de novo mutation in the index patient. Using whole-exome sequencing, we identified a heterozygous missense variant in CST6 in DNA samples from the index patient and her affected son. In line with family history, the variant was not present in samples from her parents. CST6 codes for cystatin M/E, a cysteine protease inhibitor. Patient keratinocytes showed increased expression of cathepsin genes CTSL and CTSV and reduced expression of transglutaminase genes TGM1 and TGM3. A relative gain of active, cleaved transglutaminases was found in patient keratinocytes compared to control cells. The variant found in CST6 is expected to affect protein targeting and results in marked disruption of the balance between cystatin M/E activity and its target proteases and eventually transglutaminases 1 and 3. This disturbance leads to an impairment of terminal epidermal differentiation and proper hair shaft formation seen in KFSD.
摘要：
毛囊角化病（KFSD）是一种罕见的角化病，在大多数情况下具有X连锁隐性遗传。已在MBTPS2中描述了引起X连接的KFSD的致病变体，MBTPS2是膜结合的锌金属蛋白酶的基因，该基因参与对控制转录重要的固醇调节元件结合蛋白的裂解。很少有家族被鉴定为KFSD的常染色体显性遗传。我们介绍了一个具有KFSD表型的奥地利家族的两个成员，一位母亲和她的儿子。她的父母没有发现这种疾病，指向索引患者中具有从头突变的显性遗传。使用全外显子组测序，我们在确诊患者及其患病儿子的DNA样本中鉴定出CST6中的一个杂合错义变异.根据家族病史,该变异体不存在于她父母的样本中.胱抑素M/E的CST6代码,半胱氨酸蛋白酶抑制剂.患者角质形成细胞显示组织蛋白酶基因CTSL和CTSV的表达增加，转谷氨酰胺酶基因TGM1和TGM3的表达减少。活跃的相对增益，与对照细胞相比，在患者角质形成细胞中发现了裂解的转谷氨酰胺酶。预期在CST6中发现的变体影响蛋白质靶向并导致胱抑素M/E活性与其靶蛋白酶和最终转谷氨酰胺酶1和3之间的平衡的显著破坏。这种干扰导致在KFSD中看到的终末表皮分化和适当的毛干形成受损。
