Loss‐of‐function mutations in CST6 cause dry skin, desquamation and abnormal keratosis without hypotrichosis
Loss‐of‐function mutations in CST6 cause dry skin, desquamation and abnormal keratosis without hypotrichosis
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CST6的功能缺失突变导致皮肤干燥、脱皮和异常角化病，而无皮肤机能减退
DOI：
10.1111/cge.14265
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发表时间：
2022-11
影响因子：
3.5
通讯作者：
Xuan Wang;Jun Liu;Junyi Chen;Xueyan Xu;Yadan Zhong;Yingping Xu;P. Lu;Jiajian Zhou;Zhimiao Lin;Bin Yang;Chao Yang
中科院分区：
文献类型：
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作者：
Xuan Wang;Jun Liu;Junyi Chen;Xueyan Xu;Yadan Zhong;Yingping Xu;P. Lu;Jiajian Zhou;Zhimiao Lin;Bin Yang;Chao Yang
Cystatin M/E（由 CST6 基因编码）是一种半胱氨酸蛋白酶抑制剂，主要通过直接调节组织蛋白酶 V、组织蛋白酶 L 和 legumain 活性，对不受控制的蛋白水解发挥调节和保护作用。先前的研究表明，CST6 可能通过抑制相应同源靶蛋白酶的活性，在表皮分化和毛囊形成中发挥调节作用。然而，直到最近，研究表明 CST6 基因功能的丧失或获得会导致人类皮肤干燥并伴有少毛症。在此，我们报道了两名华裔兄弟姐妹的皮肤干燥、脱屑和角化异常，但没有少毛症。通过应用全外显子组测序，我们确定 CST6 基因中的纯合功能丧失突变 c.251G > A (p.Gly84Asp) 是潜在的遗传原因。进一步的荧光酶测定表明，突变型半胱氨酸蛋白酶抑制剂 M/E 蛋白失去了对组织蛋白酶的蛋白酶活性的抑制功能。而且，小鼠体内相应的突变导致过度角质化、脱屑、皮肤屏障功能受损、角质形成细胞异常增殖和分化。总之，CST6基因中的纯合错义突变c.251G>A导致皮肤干燥、脱屑以及皮肤角化异常，促进了我们对蛋白酶-抗蛋白酶平衡在人类皮肤疾病中的作用的认识。
Cystatin M/E (encoded by the CST6 gene) is a cysteine protease inhibitor, that exerts regulatory and protective effects against uncontrolled proteolysis mainly by directly regulating cathepsin V, cathepsin L, and legumain activities. Previous studies have suggested that CST6 may exert a regulatory role in epidermal differentiation and hair follicle formation by inhibiting the activity of respective cognate target proteases. However, until recently, studies have revealed that loss‐ or gain‐of‐function of the CST6 gene causes dry skin with hypotrichosis in humans. Here, we reported two siblings of Chinese origin with dry skin, desquamation and abnormal keratosis without hypotrichosis. By applying whole‐exome sequencing, we identified homozygous loss‐of‐function mutation c.251G > A (p.Gly84Asp) in the CST6 gene as the underlying genetic cause. Further fluorimetric enzyme assays demonstrated the mutant cystatin M/E protein lost its inhibitory function on the protease activity of cathepsins. Moreover, the corresponding mutation in mice resulted in excessive cornification, desquamation, impaired skin barrier function, and abnormal proliferation and differentiation of keratinocytes. In conclusion, the homozygous missense mutation c.251G > A in CST6 gene resulted in dry skin, desquamation, as well as abnormal keratosis of the skin, promoting our understanding of the role of protease‐antiprotease balance in human skin disorders.