Homozygous ITGA3 Missense Mutation in Adults in a Family with Syndromic Epidermolysis Bullosa

Epidermolysis bullosa (EB), the prototype of skin fragility disorders, manifests with blistering and erosions of the skin and mucous membranes. In some cases, the clinical manifestations are limited to the skin, i.e., being non-syndromic, while in others the skin manifestations are associated with extracutaneous findings, thus being syndromic. The classic forms of EB are associated with 16 distinct genes expressed in the cutaneous basement membrane zone. One such gene is ITGA3 encoding alpha3 integrin subunit, which combines with beta1 subunit to form alpha3beta1 integrin. Mutations in the ITGA3 gene have been reported in 10 cases with EB, and the characteristic feature in the majority of these patients is severe respiratory and renal involvement that can lead to the early postnatal demise of the affected individuals. This subtype of EB, known as EB-RR, has also been dubbed as ILNEB (interstitial lung disease, nephrotic syndrome, and epidermolysis bullosa) (OMIM 614748). The pathogenic sequence variants in these cases are characteristically loss-of-function mutations, and EB due to ITGA3 mutations has been considered to be a severe lethal condition. In this study, we report two adult males, 45 and 30 years of age, with EB associated with a homozygous missense mutation in ITGA3.

大疱性表皮松解症（Epidermolysis bullosa, EB）是皮肤脆性疾病（skin fragility disorders）的原型，以皮肤及黏膜出现水疱与糜烂为核心临床表现。部分病例的临床表现仅局限于皮肤，即非综合征型；另一部分病例则伴随皮肤外表现，属于综合征型。经典型EB与皮肤基底膜区表达的16种不同基因相关，其中之一为编码α3整合素亚基（alpha3 integrin subunit）的ITGA3基因，该基因产物可与β1亚基（beta1 subunit）结合形成α3β1整合素（alpha3beta1 integrin）。目前已有10例携带ITGA3基因突变的EB病例被报道，此类患者的典型特征为出现严重呼吸与肾脏受累，可导致受累个体出生后早期死亡。该EB亚型被称为EB-RR，也被命名为ILNEB（间质性肺疾病、肾病综合征及大疱性表皮松解症），对应的OMIM编号为614748。此类病例的致病性序列变异多为功能丧失型突变（loss-of-function mutations），由ITGA3突变导致的EB被认为是一种严重的致死性疾病。本研究报道2例成年男性EB患者，年龄分别为45岁与30岁，其致病原因为ITGA3基因的纯合错义突变（homozygous missense mutation）。