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Confirming the recessive inheritance of PERP‐related erythrokeratoderma
Clinical Genetics ( IF 3.5 ) Pub Date : 2020-01-12 , DOI: 10.1111/cge.13699 Nisha Patel 1 , Salim Alkeraye 2 , Eman Alobeid 1 , Tarfa Alshidi 1 , Rana Helaby 1 , Firdous Abdulwahab 1 , Hanan E Shamseldin 1 , Fowzan S Alkuraya 1
Clinical Genetics ( IF 3.5 ) Pub Date : 2020-01-12 , DOI: 10.1111/cge.13699 Nisha Patel 1 , Salim Alkeraye 2 , Eman Alobeid 1 , Tarfa Alshidi 1 , Rana Helaby 1 , Firdous Abdulwahab 1 , Hanan E Shamseldin 1 , Fowzan S Alkuraya 1
Affiliation
Erythrokeratoderma (EK) is heterogeneous clinical entity characterized by excessive scaling with resulting erythrokeratotic plaques. Several genes have been linked to EK and they encode a number of proteins that are important for the integrity of the keratinocyte layer of the epidermis. PERP is a transcription factor that is activated by both p53 and p63. However, its deficiency in a mouse model appears to only recapitulate p63‐mediated role in skin development and organization. We report an extended multiplex consanguineous family in which an EK phenotype with a striking similarity to that observed in Perp−/− mice, is mapped to an autozygous region on chromosome 6 that spans PERP. Whole‐exome sequencing revealed a novel variant in PERP that fully segregated with the phenotype. Functional analysis of patient‐ and control‐derived keratinocytes revealed a deleterious effect of the identified variant on the intracellular localization of PERP. A previous report showed that PERP mutation causes a dominant form of keratoderma but a single patient in that report with a homozygous variant in PERP suggests that recessive inheritance is also possible. Our results, therefore, support the establishment of an autosomal recessive PERP‐related EK phenotype in humans.
中文翻译:
确认PERP相关性红皮角化病的隐性遗传
红皮角化病(EK)是异质性临床实体,其特征在于过度结垢并导致红斑角化斑块。几个基因已经与EK相连,它们编码许多蛋白质,这些蛋白质对于表皮角质形成细胞层的完整性很重要。PERP是被p53和p63激活的转录因子。但是,它在小鼠模型中的缺陷似乎只能概括p63介导的在皮肤发育和组织中的作用。我们报道了一个扩展的多重近亲家庭,其中一个与在Perp -/-小鼠中观察到的惊人相似的EK表型被映射到跨越PERP的6号染色体上的一个纯合子区域。全外显子组测序揭示了PERP中的一种新型变异与表型完全隔离。患者和对照来源的角质形成细胞的功能分析显示,已鉴定的变体对PERP的细胞内定位具有有害作用。先前的报道表明PERP突变会导致角化病的显性形式,但是该报告中只有一名患者具有PERP纯合突变,这也暗示了隐性遗传也是可能的。因此,我们的结果支持在人类中建立常染色体隐性PERP相关的EK表型。
更新日期:2020-03-26
中文翻译:
确认PERP相关性红皮角化病的隐性遗传
红皮角化病(EK)是异质性临床实体,其特征在于过度结垢并导致红斑角化斑块。几个基因已经与EK相连,它们编码许多蛋白质,这些蛋白质对于表皮角质形成细胞层的完整性很重要。PERP是被p53和p63激活的转录因子。但是,它在小鼠模型中的缺陷似乎只能概括p63介导的在皮肤发育和组织中的作用。我们报道了一个扩展的多重近亲家庭,其中一个与在Perp -/-小鼠中观察到的惊人相似的EK表型被映射到跨越PERP的6号染色体上的一个纯合子区域。全外显子组测序揭示了PERP中的一种新型变异与表型完全隔离。患者和对照来源的角质形成细胞的功能分析显示,已鉴定的变体对PERP的细胞内定位具有有害作用。先前的报道表明PERP突变会导致角化病的显性形式,但是该报告中只有一名患者具有PERP纯合突变,这也暗示了隐性遗传也是可能的。因此,我们的结果支持在人类中建立常染色体隐性PERP相关的EK表型。