Mutations in PLOD3, encoding lysyl hydroxylase 3, cause a complex connective tissue disorder including recessive dystrophic epidermolysis bullosa-like blistering phenotype with abnormal anchoring fibrils and type VII collagen deficiency
Mutations in PLOD3, encoding lysyl hydroxylase 3, cause a complex connective tissue disorder including recessive dystrophic epidermolysis bullosa-like blistering phenotype with abnormal anchoring fibrils and type VII collagen deficiency
复制标题
DOI：
10.1016/j.matbio.2018.11.006
复制
发表时间：
2019-08-01
期刊：
影响因子：
6.9
通讯作者：
Uitto, Jouni
中科院分区：
文献类型：
--
作者：
Vahidnezhad, Hassan;Youssefian, Leila;Uitto, Jouni
大疱性表皮松解症(EB)是遗传性皮肤脆性疾病的范例，与多达20个不同基因的突变有关。其中一种临床变异型，隐性营养不良EB(RDEB)，表现为致密层下起泡，并伴有由于COL7A1突变导致的锚定纤维改变。在这项研究中，我们描述了一名具有广泛结缔组织异常的患者，包括与RDEB相似的皮肤起泡。全外显子组测序结合全基因组纯合性图谱，鉴定出编码赖氨酸羟基酶3(LH3)的PLOD3存在纯合错义突变。之前与RDEB相关的COL7A1基因没有检测到突变。在患者的皮肤和成纤维细胞培养中，LH3的水平显著降低。皮肤起泡发生在致密层下方，与不同密度和形态的锚定纤维有关。皮肤中III型胶原的表达水平明显降低。对羟基赖氨酸及其糖基化衍生物(半乳糖基-羟基赖氨酸和葡萄糖基-半乳糖基-羟基赖氨酸)的分析表明，糖基化的羟基赖氨酸显著减少。总而言之，这些发现表明PLOD3突变可以导致结缔组织疾病谱中营养不良的EB样表型，并将其添加到与皮肤脆性相关的候选基因列表中。(C)2018爱思唯尔B.V.保留所有权利。
Epidermolysis bullosa (EB), the paradigm of heritable skin fragility disorders, is associated with mutations in as many as 20 distinct genes. One of the clinical variants, recessive dystrophic EB (RDEB), demonstrates sub-lamina densa blistering accompanied by alterations in anchoring fibrils due to mutations in COL7A1. In this study, we characterized a patient with widespread connective tissue abnormalities, including skin blistering similar to that in RDEB. Whole exome sequencing, combined with genome-wide homozygosity mapping, identified a homozygous missense mutation in PLOD3 encoding lysyl hydroxylase 3 (LH3). No mutations in COL7A1, the gene previously associated with RDEB, were detected. The level of LH3 was dramatically reduced in the skin and fibroblast cultures from the patient. The blistering in the skin occurred below the lamina densa and was associated with variable density and morphology of anchoring fibrils. The level of type VII collagen expression in the skin was markedly reduced. Analysis of hydroxylysine and its glycosylated derivatives (galactosyl-hydroxylysine and glucosyl-galactosyl-hydroxylysine) revealed marked reduction in glycosylated hydroxylysine. Collectively, these findings indicate that PLOD3 mutations can result in a dystrophic EB-like phenotype in the spectrum of connective tissue disorders and add it to the list of candidate genes associated with skin fragility. (C) 2018 Elsevier B.V. All rights reserved.