Mutations in γ-secretase subunit-encoding PSENEN underlie Dowling-Degos disease associated with acne inversa
Mutations in γ-secretase subunit-encoding PSENEN underlie Dowling-Degos disease associated with acne inversa
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DOI：
10.1172/jci90667
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发表时间：
2017-04-03
影响因子：
15.9
通讯作者：
Betz, Regina C.
中科院分区：
文献类型：
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作者：
Ralser, Damian J.;Basmanav, F. Buket Ue.;Betz, Regina C.
Dowling-Degos病（DDD）是一种常染色体显性的皮肤色素沉着疾病，与角蛋白5 （KRT5）、蛋白O-聚焦转移酶1 （POFUT1）或蛋白O-葡萄糖基转移酶1 （POGLUT1）突变有关。本研究中，我们在6例不相关的DDD患者和家族中发现了6个编码早老素增强蛋白2的PSENEN杂合截断突变，其中KRT5、POFUT1和POGLUT1突变已被排除。进一步的检查显示，滤泡性角化过度的组织病理学特征将这6例患者与先前研究的DDD患者区分开来。斑马鱼幼体中psenen的敲除导致了一种类似人类DDD的分散色素沉着的表型。在发育中的斑马鱼幼虫中，对色素细胞的体内监测表明，黑色素细胞迁移和分化的紊乱是与PSENEN相关的DDD发病机制的基础。PSENEN突变携带者中有6人患有共病性反性痤疮（AI），这是一种炎症性毛囊疾病，并且有尼古丁滥用史和/或肥胖史，这些都是已知的AI触发因素。以前，PSENEN突变在家族性AI中被发现，并且DDD和AI的共同表现已经报道了几十年。目前的研究表明，PSENEN突变确实可以导致DDD和AI的共同表现，这可能是由AI的易感因素引发的。因此，本报告描述了PSENEN突变携带者的DDD亚表型与AI易感性增加相关。
Dowling-Degos disease (DDD) is an autosomal-dominant disorder of skin pigmentation associated with mutations in keratin 5 (KRT5), protein O-fucosyltransferase 1 (POFUT1), or protein O-glucosyltransferase 1 (POGLUT1). Here, we have identified 6 heterozygous truncating mutations in PSENEN, encoding presenilin enhancer protein 2, in 6 unrelated patients and families with DDD in whom mutations in KRT5, POFUT1, and POGLUT1 have been excluded. Further examination revealed that the histopathologic feature of follicular hyperkeratosis distinguished these 6 patients from previously studied individuals with DDD. Knockdown of psenen in zebrafish larvae resulted in a phenotype with scattered pigmentation that mimicked human DDD. In the developing zebrafish larvae, in vivo monitoring of pigment cells suggested that disturbances in melanocyte migration and differentiation underlie the DDD pathogenesis associated with PSENEN. Six of the PSENEN mutation carriers presented with comorbid acne inversa (AI), an inflammatory hair follicle disorder, and had a history of nicotine abuse and/or obesity, which are known trigger factors for AI. Previously, PSENEN mutations were identified in familial AI, and comanifestation of DDD and AI has been reported for decades. The present work suggests that PSENEN mutations can indeed cause a comanifestation of DDD and AI that is likely triggered by predisposing factors for AI. Thus, the present report describes a DDD subphenotype in PSENEN mutation carriers that is associated with increased susceptibility to AI.