确定导致大疱性表皮松解伴幽门闭锁的ITGB4基因中两个罕见和新的大缺失。

PubMed ID
发表日期 2016年Apr月

原始出处 实验皮肤病学
Experimental dermatology
作者 Mencía  Ángeles  García  Marta  García  Eva  Llames  Sara  Charlesworth  Alexandra  de Lucas  Raúl  Vicente  Asunción  Trujillo-Tiebas  María José  Coto  Pablo  Costa  Marta  Vera  Ángel  López-Pestaña  Arantxa  Murillas  Rodolfo  Meneguzzi  Guerrino  Jorcano  José Luis  Conti  Claudio J  Escámez Toledano  María José  del Río Nechaevsky  Marcela 

文献标题 确定导致大疱性表皮松解伴幽门闭锁的ITGB4基因中两个罕见和新的大缺失。
Identification of two rare and novel large deletions in ITGB4 gene causing epidermolysis bullosa with pyloric atresia.

文献摘要

大疱性表皮松解伴幽门闭锁(EB-PA)是一种罕见的常染色体隐性遗传病,其预后从致命到非常轻微不等。EB-PA分为单纯型(EBS-PA:OMIM#612138)和连接型(JEB-PA:OMIM#226730),由ITGA6、ITGB4和PLEC基因突变引起。我们报告了6例EB-PA患者的分析,其中包括两对双卵双胞胎。进行皮肤免疫荧光表位定位,然后进行PCR和ITGB4基因直接测序。其中两名患者出现与错义ITGB4基因突变相关的非致死性EB-PA。对于其他四例,由于多种ITGB4新突变(2个大的缺失、1个剪接位点突变和3个错义突变),出生后早期死亡与β4整合素的完全缺乏有关。其中一个缺失跨越278 bp,是迄今为止报道的该基因最大的缺失之一。值得注意的是,我们还首次发现ITGB4基因中一个新突变的创始人效应。我们在ITGB4基因中发现了6个新的突变,将其添加到突变数据库中。我们的结果揭示了基因型-表型相关性,这有助于对这种异质性疾病的分子理解,这是预后的关键问题,也是EB治疗新的循证治疗选择的发展。


Epidermolysis bullosa with pyloric atresia (EB-PA) is a rare autosomal recessive hereditary disease with a variable prognosis from lethal to very mild. EB-PA is classified into Simplex form (EBS-PA: OMIM #612138) and Junctional form (JEB-PA: OMIM #226730), and it is caused by mutations in ITGA6, ITGB4 and PLEC genes. We report the analysis of six patients with EB-PA, including two dizygotic twins. Skin immunofluorescence epitope mapping was performed followed by PCR and direct sequencing of the ITGB4 gene. Two of the patients presented with non-lethal EB-PA associated with missense ITGB4 gene mutations. For the other four, early postnatal demise was associated with complete lack of β4 integrin due to a variety of ITGB4 novel mutations (2 large deletions, 1 splice-site mutation and 3 missense mutations). One of the deletions spanned 278 bp, being one of the largest reported to date for this gene. Remarkably, we also found for the first time a founder effect for one novel mutation in the ITGB4 gene. We have identified 6 novel mutations in the ITGB4 gene to be added to the mutation database. Our results reveal genotype-phenotype correlations that contribute to the molecular understanding of this heterogeneous disease, a pivotal issue for prognosis and for the development of novel evidence-based therapeutic options for EB management.


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