Project of Hereditary Keratinizing Disorders

转氨酶3是一种分子量约为77 kDa的酶。该酶是钙和巯基依赖性酶，催化蛋白质的赖氨酸和谷氨酰胺残基之间的反应。因此，在皮质细胞包膜蛋白前体如外皮蛋白、富含脯氨酸的小蛋白、弹力素、半胱氨酸蛋白酶抑制剂A和兜甲蛋白之间产生异二肽交联。众所周知，转氨酶3分布于复层表皮的颗粒层。这种分布模式与兜甲蛋白几乎相同。皮肤角化疾病分为两大类。一种是遗传性角化疾病，另一种是非遗传性角化疾病。遗传性角化病有遗传性鱼鳞病、Darier病、掌跖角化过度、汗孔角化病等，而大疱性先天性鱼鳞病样红皮病、环状表皮性鱼鳞病、板层鱼鳞病、部分掌跖角化病、先天性甲肥厚、Vohwinkel综合征、部分进行性系统性红斑角化病、目前已知Darier病和Hailey-Hailey病是由特定基因的缺失和/或点突变引起的。相反，大多数遗传性角化疾病的基因尚不清楚。我推测转氨酶3基因是遗传性角化疾病的致病基因之一。我试着做转谷氨酰胺酶3基因的敲除小鼠。我们从小鼠表皮cDNA文库中筛选出小鼠转氨酶3 cDNA。下一步我们将从129 SV小鼠基因组文库中克隆基因组DNA，并最终构建靶向载体。

Transglutaminase 3 is an enzyme of which molecular weight is about 77 kDa. This enzyme is calcium-and thiol-dependent one and catalyze between lysine and glutamine residues of proteins. Therefore, iso-dipeptide crosslinks are made between cornified cell envelope protein precursors such as involucrin, small proline-rich proteins, elafin, cystatin A and loricrin. It is well known that transglutaminase 3 is distributed and granular layer of stratified epidermis. And this distribution pattern is almost same as loricrin.Keratinizing disorders in skin are divided in 2 major groups. One is hereditary keratinizing disorders and another is non-hereditary keratinizing ones. Hereditary keratinizing disorders are hereditary ichthyoses, Darier disease, palmoplantar hyperkeratosis, porokeratosis and so on. However, diseases such as bullous congenital ichthyosiform erythroderma, annular epidermolytic ichthyosis, lamellar ichthyosis, some of palmoplantar karatodermas, pachyonychia congenita, Vohwinkel syndrome, some of progressive systemic erythrokeratoderma, Darier disease and Hailey-Hailey disease are now known to be caused by deletions and/or point mutations of specific genes. In contrast, the responsible genes for most of the hereditary keratinizing disorders are not known. I postulate the gene for transglutaminase 3 enzyme is one of the responsible genes for the hereditary keratinizing disorders. I try to make the knock out mouse of transglutaminase 3 gene. We screened the mouse transglutaminase 3 cDNA from mouse epidermis cDNA library. We are going to get a clone of genomic DNA from 129SV mouse genomic library next and finally make a targeting vector.