nature-genetic201211-14

来自英国邓迪大学的Irwin McLean及其同事发现参与膜泡运输的细胞溶质蛋白的编码基因AAGAB的异质性功能丧失性突变,该突变造成点状掌跖角化病。进一步研究发现沉默角质细胞中的AAGAB基因导致细胞过度增殖,并伴随表皮生长因子受体的表达高度上调。相关的研究论文于10月14日在线发表在《Nature Genetics》期刊上。

-2012年11月《自然-遗传》

中文翻译


【题目】AAGAB基因的单倍体剂量不足效应导致临床异质性的点状掌跖角化病

【译文】掌跖角化病(PPKs)是一类难以诊断且无法治疗的遗传性皮肤病。点状掌跖角化病的特点是皮肤发生局部角质化的病变,手掌和脚掌肥厚。我们对患有常染色体显性的点状掌跖角化病的18个家族进行研究,发现发生不均一性的AAGAB基因功能能丧失性突变,AAGAB基因编码了一个α-和γ-衔接蛋白-结合蛋白p34,它定位于15q22区域中先前发现的连锁位点上。α-和γ-衔接蛋白-结合蛋白p34,是一个具有Rab样GTP酶结构域的细胞溶质蛋白,研究发现它均能与网格蛋白衔接蛋白复合物结合,这表明它在膜泡运输中具有重要作用。超微结构分析在病灶性表皮中发现异常的胞内囊泡。使用免疫组织化学在点状病灶中发现细胞过度增殖。将角质细胞中的AAGAB基因沉默后,则导致细胞分裂加快,且极大地提高了表皮生长因子受体(EGFR)的表达水平和酪氨酸磷酸化水平。本研究假定p34蛋白的缺失可能会破坏生长因子受体,如EGFR的内吞循环作用,从而导致细胞信号放大和细胞过度增殖。

英文原稿


[Title]: Haploinsufficiency for AAGAB causes clinically heterogeneous forms of punctate palmoplantar keratoderma

[Authors]: Elizabeth Pohler, Ons Mamai, Jennifer Hirst, Mozheh Zamiri, Helen Horn, Toshifumi Nomura, Alan D Irvine, Benvon Moran, Neil J Wilson, Frances J D Smith, Christabelle S M Goh, Aileen Sandilands, Christian Cole, Geoffrey J Barton, Alan T Evans, Hiroshi Shimizu, Masashi Akiyama, Mitsuhiro Suehiro, Izumi Konohana, Mohammad Shboul, Sebastien Teissier, Lobna Boussofara, Mohamed Denguezli, Ali Saad, Moez Gribaa, Patricia J Dopping-Hepenstal, John A McGrath, Sara J Brown, David R Goudie, Bruno Reversade, Colin S Munro & W H Irwin McLean

[Abstract]: Palmoplantar keratodermas (PPKs) are a group of disorders that are diagnostically and therapeutically problematic in dermatogenetics. Punctate PPKs are characterized by circumscribed hyperkeratotic lesions on the palms and soles with considerable heterogeneity. In 18 families with autosomal dominant punctate PPK, we report heterozygous loss-of-function mutations in AAGAB, encoding α- and γ-adaptin–binding protein p34, located at a previously linked locus at 15q22. α- and γ-adaptin–binding protein p34, a cytosolic protein with a Rab-like GTPase domain, was shown to bind both clathrin adaptor protein complexes, indicating a role in membrane trafficking. Ultrastructurally, lesional epidermis showed abnormalities in intracellular vesicle biology. Immunohistochemistry showed hyperproliferation within the punctate lesions. Knockdown of AAGAB in keratinocytes led to increased cell division, which was linked to greatly elevated epidermal growth factor receptor (EGFR) protein expression and tyrosine phosphorylation. We hypothesize that p34 deficiency may impair endocytic recycling of growth factor receptors such as EGFR, leading to increased signaling and cellular proliferation.

原文地址

http://www.nature.com/ng/journal/v44/n11/full/ng.2444.html

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