Mutations in KRT5 and KRT14 cause epidermolysis bullosa simplex in 75% of the patients
Mutations in KRT5 and KRT14 cause epidermolysis bullosa simplex in 75% of the patients
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DOI：
10.1111/j.1365-2133.2010.10146.x
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发表时间：
2011-03-01
影响因子：
10.3
通讯作者：
Jonkman, M. F.
中科院分区：
文献类型：
--
作者：
Bolling, M. C.;Lemmink, H. H.;Jonkman, M. F.
单纯大疱性表皮病（epiderbullosa simplex，EBS）是一种机械性大疱性遗传性皮肤病，可能由编码基底表皮角蛋白5（K5）和14（K14）的基因KRT 5和KRT 14突变引起。存在三种主要的EBS临床亚型，其在皮肤起泡的发病、分布和严重程度上不同。KRT 5和KRT 14突变的先前报道表明突变的位置和相关的EBS表型的严重程度之间的相关性。目的KRT 5/KRT 14突变的患病率和基因型-表型相关性在最大的组织确认的EBS人群中进行调查。扩增确定的不相关EBS先证者，然后进行直接测序和产物长度分析。免疫荧光显微镜对患者的皮肤活检与抗体对K5和K14进行研究蛋白expression.ResultsIn 57的76（75%）先证者41个不同的KRT 5和KRT 14突变，其中12个是新的。影响K5和K14的杆结构域的高度保守的螺旋边界基序，特别是K14螺旋起始基序的突变与EBS Dowling-Meara表型相关。在21例EBS先证者（37%）中，突变是新发的。在19个先证者（25%）KRT 5或KRT 14突变excluded.ConclusionsThe表型-基因型相关性观察到在这个大的EBS人口强调角蛋白组装的螺旋边界图案的重要性。只有四分之三的活检证实的EBS先证者有KRT 5或KRT 14突变，表明EBS的遗传异质性。替代基因候选人进行了讨论。
P>BackgroundEpidermolysis bullosa simplex (EBS) is a mechanobullous genodermatosis that may be caused by mutations in the genes KRT5 and KRT14 encoding the basal epidermal keratins 5 (K5) and 14 (K14). Three main clinical subtypes of EBS exist, differing in onset, distribution and severity of skin blistering. Previous reports of KRT5 and KRT14 mutations suggest a correlation between the location of the mutation and the severity of the associated EBS phenotype.ObjectivesThe prevalence of KRT5/KRT14 mutations and the genotype-phenotype correlation in the largest tissue-confirmed EBS population is investigated.MethodsKRT5 and KRT14 genomic DNA and cDNA sequences of 76 clinically well-defined unrelated EBS probands were amplified and then subjected to direct sequencing and product length analysis. Immunofluorescence microscopy on patients' skin biopsies with antibodies against K5 and K14 was performed to study protein expression.ResultsIn 57 of 76 (75%) probands 41 different KRT5 and KRT14 mutations were identified, of which 12 were novel. Mutations affecting the highly conserved helix boundary motifs of the rod domains of K5 and K14, and the K14 helix initiation motif in particular, were associated with the severest, EBS Dowling-Meara, phenotype. In 21 EBS probands (37%) the mutation was de novo. In 19 probands (25%) KRT5 or KRT14 mutations were excluded.ConclusionsThe phenotype-genotype correlation observed in this large EBS population underscores the importance of helix boundary motifs for keratin assembly. Only three-quarters of biopsy-confirmed EBS probands have KRT5 or KRT14 mutations, indicating genetic heterogeneity in EBS. Alternative gene candidates are discussed.