ENPP1 Mutation Causes Recessive Cole Disease by Altering Melanogenesis
ENPP1 Mutation Causes Recessive Cole Disease by Altering Melanogenesis
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DOI：
10.1016/j.jid.2017.08.045
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发表时间：
2018-02-01
影响因子：
6.5
通讯作者：
Reversade, Bruno
中科院分区：
文献类型：
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作者：
Chourabi, Marwa;Liew, Mei Shan;Reversade, Bruno
科尔病是一种色素沉着的遗传性皮肤病，遵循严格的显性遗传模式。在这项研究中，我们调查了8例隐性遗传后的重叠基因皮肤病。患者表现为全身色素沉着和高色素斑，类似于遗传性普遍色素沉着症，并伴有点状掌跖角化病。通过纯合子定位和全外显子组测序，在所有患者中鉴定出外核苷酸焦磷酸酶/磷酸二酯酶1 （ENPP1）双等位基因p. Cys120Arg突变。我们发现这种突变，像那些引起显性科尔病的突变一样，损害了ENPP1酶的同二聚化，这是由它的两个somatomedin- b样结构域介导的。组织学分析显示，受影响皮肤的结构和分子变化可能源于有缺陷的黑色素细胞，因为角化细胞不表达ENPP1。一致地，患者源性原代黑素细胞的rna测序分析揭示了黑素细胞发育和色素沉着信号通路的改变。因此，我们得出结论，种系ENPP1半胱氨酸特异性突变，主要影响黑素细胞谱系，导致临床谱中的色素沉着症，其中p. Cys120Arg等位基因代表一种隐性和更严重的科尔病形式。
Cole disease is a genodermatosis of pigmentation following a strict dominant mode of inheritance. In this study, we investigated eight patients affected with an overlapping genodermatosis after recessive inheritance. The patients presented with hypo- and hyperpigmented macules over the body, resembling dyschromatosis universalis hereditaria in addition to punctuate palmoplantar keratosis. By homozygosity mapping and wholeexome sequencing, a biallelic p. Cys120Arg mutation in ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) was identified in all patients. We found that this mutation, like those causing dominant Cole disease, impairs homodimerization of the ENPP1 enzyme that is mediated by its two somatomedin-B-like domains. Histological analysis revealed structural and molecular changes in affected skin that were likely to originate from defective melanocytes because keratinocytes do not express ENPP1. Consistently, RNA-sequencing analysis of patient-derived primary melanocytes revealed alterations in melanocyte development and in pigmentation signaling pathways. We therefore conclude that germline ENPP1 cysteine-specific mutations, primarily affecting the melanocyte lineage, cause a clinical spectrum of dyschromatosis, in which the p. Cys120Arg allele represents a recessive and more severe form of Cole disease.