2012年10月20日 訊 /生物谷BIOON/ --近日,，來(lái)自A*STAR分子生物生物研究所等處的研究者指出，每次當(dāng)我們發(fā)現(xiàn)促使皮膚病的新型遺傳突變時(shí),，就無(wú)疑會(huì)幫助病人或者其家庭更清楚地揭穿疾病的發(fā)病本質(zhì)。隨著科學(xué)家和醫(yī)生們的通力合作,，我們開(kāi)發(fā)出了針對(duì)罕見(jiàn)狀況的許多新型療法,。
如今研究者發(fā)現(xiàn)了一種促使皮膚層變厚的遺傳突變，其主要表現(xiàn)為手掌和足底的皮膚嚴(yán)重加厚,，影響患者的正常生活,。這種皮膚層變厚的會(huì)隨著患者的年齡增加而不斷增厚，而且會(huì)形成較大的皮膚片層,，這種皮膚損傷使患者非常疼痛以及虛弱,。
來(lái)自A*STAR的研究者同英國(guó)、日本以及突尼斯等國(guó)的研究者聯(lián)合,，發(fā)現(xiàn)了這種皮膚?。ǚQ為點(diǎn)狀掌跖角皮病，punctate PPK）是由于基因AAGAB突變引起的,，這種疾病是一種罕見(jiàn)的掌跖角化病，很多患者都受到這種疾病嚴(yán)重的影響,。
當(dāng)前基因突變的發(fā)現(xiàn)可以幫助科學(xué)家更好地理解該疾病的發(fā)病原因,，為后續(xù)的新型療法的開(kāi)發(fā)帶來(lái)了極大幫助，相關(guān)研究成果刊登于國(guó)際著名雜志Nature Genetics上,。
科學(xué)家分析了來(lái)自蘇格蘭,、日本等國(guó)的點(diǎn)狀掌跖角皮病的18個(gè)家庭的DNA樣品，揭示出了編碼蛋白p34的基因AAGAB,，其可以自皮膚中表達(dá),，在控制細(xì)胞分裂上扮演著重要角色。AAGAB的剔除可以導(dǎo)致p34的缺失,，進(jìn)而導(dǎo)致皮膚外層細(xì)胞的增殖分裂加速,。由于增加了生長(zhǎng)信號(hào)，皮膚外層就會(huì)成功產(chǎn)生表皮生長(zhǎng)因子（EGFR）,。EGFR信號(hào)的阻斷是異常細(xì)胞增殖的一個(gè)特點(diǎn),，而且這項(xiàng)研究發(fā)現(xiàn)PPK是一種增殖過(guò)度的良性形式。
研究者Bruno表示,，罕見(jiàn)的遺傳病研究通常會(huì)帶來(lái)意想不到的結(jié)果,，點(diǎn)狀掌跖角皮病病人的表型與尋常性疣的表現(xiàn)相似，我們就推測(cè)HPV可能也通過(guò)阻斷點(diǎn)狀掌跖角皮病的發(fā)病通路來(lái)進(jìn)行皮膚增殖的誘導(dǎo),，研究發(fā)現(xiàn)闡明了EGFR,，皮膚癌的標(biāo)志,，也為解釋點(diǎn)狀掌跖角皮病的發(fā)病提供了一些線索。（生物谷Bioon.com）
編譯自：Mutation That Causes Skin Hyperproliferation Identified
doi:10.1038/ng.2444
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PMID:
Haploinsufficiency for AAGAB causes clinically heterogeneous forms of punctate palmoplantar keratoderma
Elizabeth Pohler,1 Ons Mamai,2, 3 Jennifer Hirst,4 Mozheh Zamiri,5 Helen Horn,6 Toshifumi Nomura,7 Alan D Irvine,8, 9 Benvon Moran,8 Neil J Wilson,1 Frances J D Smith,1 Christabelle S M Goh,1 Aileen Sandilands,1 Christian Cole,1, 10 Geoffrey J Barton,10 Alan T Evans,11 Hiroshi Shimizu,7 Masashi Akiyama,12 Mitsuhiro Suehiro,13 Izumi Konohana,14 Mohammad Shboul,3 Sebastien Teissier,3 Lobna Boussofara,15 Mohamed Denguezli,15 Ali Saad,2 Moez Gribaa,2 Patricia J Dopping-Hepenstal,16 John A McGrath,17 Sara J Brown,1 David R Goudie,18 Bruno Reversade,3, 19 Colin S Munro20 & W H Irwin McLean1 et al.
Palmoplantar keratodermas (PPKs) are a group of disorders that are diagnostically and therapeutically problematic in dermatogenetics1, 2, 3. 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.
