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.

中文翻译：

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编码赖氨酰羟化酶 3 的 PLOD3 突变会导致复杂的结缔组织疾病，包括隐性营养不良性大疱性表皮松解症样水疱表型，具有异常锚定纤维和 VII 型胶原蛋白缺乏症。

大疱性表皮松解症 (EB) 是遗传性皮肤脆性病症的范例，与多达 20 个不同基因的突变有关。其中一种临床变异，隐性营养不良性 EB (RDEB)，表现出致密层下水疱，伴随着由于 COL7A1 突变引起的锚定纤维的改变。在这项研究中，我们描述了一名患有广泛结缔组织异常的患者，包括类似于 RDEB 的皮肤水疱。全外显子组测序结合全基因组纯合性作图，确定了编码赖氨酰羟化酶 3 (LH3) 的 PLOD3 中的纯合错义突变。未检测到 COL7A1（先前与 RDEB 相关的基因）中的突变。患者皮肤和成纤维细胞培养物中的 LH3 水平显着降低。皮肤中的水泡发生在致密层下方，并且与锚定原纤维的密度和形态不同有关。皮肤中VII型胶原蛋白的表达水平显着降低。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）的分析表明糖基化羟基赖氨酸显着减少。总的来说，这些发现表明 PLOD3 突变可导致结缔组织疾病谱中的营养不良 EB 样表型，并将其添加到与皮肤脆弱性相关的候选基因列表中。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）的分析表明糖基化羟基赖氨酸显着减少。总的来说，这些发现表明 PLOD3 突变可导致结缔组织疾病谱中的营养不良 EB 样表型，并将其添加到与皮肤脆弱性相关的候选基因列表中。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）的分析表明糖基化羟基赖氨酸显着减少。总的来说，这些发现表明 PLOD3 突变可导致结缔组织疾病谱中的营养不良 EB 样表型，并将其添加到与皮肤脆弱性相关的候选基因列表中。