Mutation analysis and molecular genetics of epidermolysis bullosa
Mutation analysis and molecular genetics of epidermolysis bullosa
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DOI：
10.1016/s0945-053x(98)00005-5
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发表时间：
1999-02-01
期刊：
影响因子：
6.9
通讯作者：
Uitto, J
中科院分区：
文献类型：
--
作者：
Pulkkinen, L;Uitto, J
皮肤基底膜区(BMZ)由许多附着结构组成，这些附着结构对表皮与真皮之间的稳定结合至关重要。这些包括半桥粒、锚定细丝和锚定纤维，它们形成了一个从基底层角质形成细胞内环境穿过真皮-表皮基底膜延伸到下面的真皮的互连网络。这种网络结构中的异常，例如由于相应基因中的遗传损伤，可能导致皮肤在皮肤BMZ水平上的脆弱性。这种疾病的原型是大疱性表皮松解症(EB)，这是一组以皮肤脆性和水泡为特征的异质性遗传病，常伴有皮外表现，遗传方式为常染色体显性遗传或常染色体隐性遗传。根据表型表现、疾病严重程度和皮肤BMZ内组织分离程度的不同，EB被分为临床上不同的亚型，包括单纯型、半桥粒变异型、交界型和营养不良变异型。BMZ基因/蛋白系统的阐明和突变检测策略的发展使我们能够识别10个不同的BMZ基因的突变，这可以解释EB的临床异质性。这些突变包括营养不良性(严重瘢痕形成)型EB中VII型胶原基因(COL7A1)的突变；致命(Herlitz)型交界型EB中层粘连蛋白5基因(LAMA3、LAMB3和LAMC2)的突变；非致死型交界型EB中XVII型胶原基因(COL17A1)的异常；伴有先天性幽门闭锁的独特半染色体型EB中整合素α6和β4的基因突变；以及与晚发性肌营养不良相关的EB中的plectin基因(PLEC1)突变。对这些基因/蛋白质系统突变的鉴定证明，它们对皮肤BMZ的整体稳定性至关重要。此外，阐明EB不同变异体的突变对于EB的精细分类、改进遗传咨询和发展基于DNA的产前检测具有直接的临床应用。(C)1999年Elsevier Science B.V./国际基质生物学学会。版权所有。
Cutaneous basement membrane zone (BMZ) consists of a number of attachment structures that are critical for stable association of the epidermis to the underlying dermis. These include hemidesmosomes, anchoring filaments and anchoring fibrils which form an interconnecting network extending from the intracellular milieu of basal keratinocytes across the dermal-epidermal basement membrane to the underlying dermis. Aberrations in this network structure, e.g. due to genetic lesions in the corresponding genes, can result in fragility of the skin at the level of the cutaneous BMZ. The prototype of such diseases is epidermolysis bullosa (EB), a heterogeneous group of genodermatoses characterized by fragility and blistering of the skin, often associated with extracutaneous manifestations, and inherited either in an autosomal dominant or autosomal recessive manner. Based on constellations of the phenotypic manifestations, severity of the disease, and the level of tissue separation within the cutaneous BMZ, EB has been divided into clinically distinct subcategories, including the simplex, hemidesmosomal, junctional and dystrophic variants. Elucidation of BMZ gene/protein systems and development of mutation detection strategies have allowed identification of mutations in 10 different BMZ genes which can explain the clinical heterogeneity of EB. These include mutations in the type VII collagen gene (COL7A1) in the dystrophic (severely scarring) forms of EB; mutations in the laminin 5 genes (LAMA3, LAMB3 and LAMC2) in a lethal (Herlitz) variant of junctional EB; aberrations in the type XVII collagen gene (COL17A1) in non-lethal forms of junctional EB; mutations in the alpha 6 and beta 4 integrin genes in a distinct hemidesmosomal variant of EB with congenital pyloric atresia; and mutations in the plectin gene (PLEC1) in a form of EB associated with late-onset muscular dystrophy. Identification of mutations in these gene/protein systems attests to their critical importance in the overall stability of the cutaneous BMZ. Furthermore, elucidation of mutations in different variants of EB has direct clinical applications in terms of refined classification, improved genetic counseling, and development of DNA-based prenatal testing in families with EB. (C) 1999 Elsevier Science B.V./International Society of Matrix Biology. All rights reserved.