Phenotypic expansion of POFUT1 loss of function mutations in a disorder featuring segmental dyspigmentation with eczematous and folliculo-centric lesions.
Phenotypic expansion of POFUT1 loss of function mutations in a disorder featuring segmental dyspigmentation with eczematous and folliculo-centric lesions.
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DOI：
10.1002/ajmg.a.61362
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发表时间：
2019-12
期刊：
影响因子：
--
通讯作者：
Choate KA
中科院分区：
文献类型：
--
作者：
Atzmony L;Zaki TD;Antaya RJ;Choate KA
薄Blaschko线马赛克疾病的外观表明，角质形成细胞前体细胞突变的发病机制。POFUT 1基因的种系杂合突变导致Dowling-Degos病（DDD），这是一种以弯曲网状色素沉着过度和毛囊为基础的病变为特征的皮肤病。POFUT 1嵌合现象至今尚未被描述。我们报告一个9岁的女性，她有节段性色素过度和色素减退的斑片，上覆湿疹斑和毛囊丘疹。采用配对的全外显子组测序的唾液和角质形成细胞从受影响的皮肤，我们发现了一种新的种系杂合POFUT 1缺失引起移码和过早的密码子终止和体细胞拷贝中性杂合性丢失20号染色体上的POFUT 1。与正常角质形成细胞相比，POFUT 1以及notch信号通路的其他关键调节因子NOTCH 1、NOTCH 2和HES 1在受影响的角质形成细胞中的表达水平降低。我们的研究结果提供了POFUT 1合子后突变和POFUT 1功能缺失突变表型扩展的第一个证据。我们表明，POFUT 1的隐性功能丧失突变产生了独特的临床表现与功能（如皮炎），在DDD的广义形式缺席。这项研究展示了镶嵌疾病的分析如何揭示已知基因的意外表型。
Appearance of mosaic disorders in thin Blaschko lines suggests that somatic mutations in keratinocyte precursors underlie their pathogenesis. Germline heterozygous mutations in POFUT1 gene cause Dowling-Degos disease (DDD), a skin disease that features flexural reticulated hyperpigmentation and follicular-based lesions. POFUT1 mosaicism has not been described to date. Here we describe a 9-year old female with segmental hyper- and hypopigmented patches with overlying eczematous plaques and follicular papules. Employing paired whole exome sequencing of saliva and keratinocytes isolated from affected skin, we found a novel germline heterozygous POFUT1 deletion causing frameshift and premature codon termination and somatic copy-neutral loss of heterozygosity on chromosome 20 encompassing POFUT1. Expression levels of POFUT1 as well as other key-regulators of the notch signaling pathway—NOTCH1, NOTCH2 and HES1— were reduced in affected keratinocytes compared to normal keratinocytes. Our findings provide the first evidence of POFUT1 post-zygotic mutation and a phenotypic expansion of POFUT1 loss of function mutations. We show that a recessive loss of function mutation in POFUT1 produces a distinct clinical presentation with features (e.g. dermatitis) that are absent in the generalized form of DDD. This study demonstrates how analysis of mosaic disorders can reveal unexpected phenotypes for known genes.
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