Elucidation of Pathogenetic Mechanisms of Severe Ichthyoses and Establishment of New Method for the Diagnosis and Prenatal Disease Detection

阐明重度鱼鳞病发病机制及建立诊断及产前疾病检测新方法

• 批准号: 10557082
• 负责人: NISHIKAWA Takeji
• 金额: $ 8.77万
• 依托单位: Keio University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10557082/
• 关键词: cornified cell envelope; gene mutation; genodermatosis; ichthyosis; immunoelectron microscopy; non-bullous congenital ichthyosiform erthroderma; prenatal diagnosis; transglutaminase 1; 非水疱型魚鱗癬様紅皮症; cornified cell envelope

Pathogenetic mechanisms of autosomal recessive congenital ichthyosis are still unknown although malformation or the cornified cell envelope arising from mutations of the transglutaminase (Tgase) 1 gene is reported to be the cause of sine cases of lamellar ichthyosis. In this study, using immunofluorescence, immunoelectron microscopic and molecular genetic techniques, pathogenetic mechanisms of several types of autosomal recessive severe ichthyosis were investigated in many affected Japanese families. Immunofluorescent and immunoelectron microscopic observations revealed that abnormality in expression and distribution of several proteins associated with cornified cell envelope formation in the epidermal keratinocytes. Heteroduplex analysis and direct sequencing or the PCR-amplified genes were performed to the putative responsible genes for the ichthyosis phenotypes from results of the morphologic observations. The mutations found were confirmed by restriction enzyme cutting and allele specific oligonucleotide hybfidization methods. In some families, precise and definite diagnosis can be made on the basis of the information of responsible genes. In addition, the results of this study contributed to the establishment of methodology of early prenatal diagnosis of the severe congenital ichthyoses.

常染色体隐性遗传性先天性鱼鳞病的发病机制仍然是未知的，虽然畸形或皮质细胞包膜所产生的转氨酶（TGase）1基因突变的报道是原因的四例板层状鱼鳞病。在这项研究中，使用免疫荧光，免疫电镜和分子遗传学技术，发病机制的几种类型的常染色体隐性遗传严重鱼鳞病在许多受影响的日本家庭进行了调查。免疫荧光和免疫电镜观察显示，在表皮角质形成细胞中，与角质形成细胞被膜形成相关的几种蛋白质的表达和分布异常。根据形态学观察结果，对可能与鱼鳞病表型相关的基因进行异源双链分析和直接测序。用限制性内切酶切割和等位基因特异性寡核苷酸杂交方法证实突变。在某些家系中，根据致病基因的信息可以作出准确、明确的诊断。本研究结果有助于建立早期产前诊断重症先天性鱼鳞病的方法学。

项目成果

Akiyama M,Smith LT,Yoneda K,Holbrook KA,Hohl D,Shimizu H.: "Periderm cells form cornified cell envelope in their regression precess during human epidermal development"J Invest Dermatol. 112. 903-909 (1999)

Akiyama M、Smith LT、Yoneda K、Holbrook KA、Hohl D、Shimizu H.：“周皮细胞在人类表皮发育过程中的回归过程中形成角化细胞包膜”J Invest Dermatol。

Tamai K, Murai T, Mayama M, Kon A, Nomura K, Sawamura D, et al: "Recurrent COL7A1 mutations in Japanese patients with dystrophic epidermolysis bulleosa : positional effects of premature termination codon mutation on clinical severity"J Invest Dermatol.

Tamai K、Murai T、Mayama M、Kon A、Nomura K、Sawamura D 等人：“日本营养不良性大疱性表皮松解症患者中复发的 COL7A1 突变：提前终止密码子突变对临床严重程度的位置影响”J Invest Dermatol。

Akiyama M. Smith LT, Yoneda K, Holbrook KA, Hohl D, Shimizu H.,: "Periderm cells from cornified cell envelope in their regression precess during human epidermal development"J. Invest Dermatol. 112. 903-909 (1999)

Akiyama M. Smith LT、Yoneda K、Holbrook KA、Hohl D、Shimizu H.，：“角化细胞包膜的周皮细胞在人类表皮发育过程中的回归过程”J。

Imada M,Shimizu H,Sasaki Y,Nishikawa T: "Three cases of Daruer's disease in a family showing marked heterogeneous clinical severity"Dermatol. 198. 167-170 (1999)

Imada M、Shimizu H、Sasaki Y、Nishikawa T：“一个家族中的三例 Daruer 病表现出明显的异质性临床严重程度”Dermatol。

Tamai K,Murai T,Mayama M,Kon A,Nomura K,Sawamura D,et al.: "Recurrent COL7A1 mutations in Japanese patients with dystrophic epidermolysis bull positional effects of premature termination codon mutations on clinical severity"J Invest Dermatol. 112. 991-993

Tamai K、Murai T、Mayama M、Kon A、Nomura K、Sawamura D 等人：“日本营养不良性表皮松解症患者中复发的 COL7A1 突变公牛过早终止密码子突变对临床严重程度的位置影响”J Invest Dermatol。