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腾讯登录Nat Genetics：鉴别出引发皮肤增生过度的遗传突变
| 导读 | 近日，来自A*STAR分子生物生物研究所等处的研究者指出，每次当我们发现促使皮肤病的新型遗传突变时，就无疑会帮助病人或者其家庭更清楚地揭穿疾病的发病本质。随着科学家和医生们的通力合作，我们开发出了针对罕见状况的许多新型疗法。<!--more-->
如今研究者发现了一种促使皮肤层变厚的遗传突变，其主要表现为手掌和足底的皮肤严重加厚，影响患者的正常生活。这种皮肤层变厚的会随着患者的年... |
近日，来自A*STAR分子生物生物研究所等处的研究者指出，每次当我们发现促使皮肤病的新型遗传突变时，就无疑会帮助病人或者其家庭更清楚地揭穿疾病的发病本质。随着科学家和医生们的通力合作，我们开发出了针对罕见状况的许多新型疗法。<!--more-->
如今研究者发现了一种促使皮肤层变厚的遗传突变，其主要表现为手掌和足底的皮肤严重加厚，影响患者的正常生活。这种皮肤层变厚的会随着患者的年龄增加而不断增厚，而且会形成较大的皮肤片层，这种皮肤损伤使患者非常疼痛以及虚弱。
来自A*STAR的研究者同英国、日本以及突尼斯等国的研究者联合，发现了这种皮肤病（称为点状掌跖角皮病，punctate PPK）是由于基因AAGAB突变引起的，这种疾病是一种罕见的掌跖角化病，很多患者都受到这种疾病严重的影响。
当前基因突变的发现可以帮助科学家更好地理解该疾病的发病原因，为后续的新型疗法的开发带来了极大帮助，相关研究成果刊登于国际著名杂志<em>Nature Genetics</em>上。
科学家分析了来自苏格兰、日本等国的点状掌跖角皮病的18个家庭的DNA样品，揭示出了编码蛋白p34的基因AAGAB，其可以自皮肤中表达，在控制细胞分裂上扮演着重要角色。AAGAB的剔除可以导致p34的缺失，进而导致皮肤外层细胞的增殖分裂加速。由于增加了生长信号，皮肤外层就会成功产生表皮生长因子（EGFR）。EGFR信号的阻断是异常细胞增殖的一个特点，而且这项研究发现PPK是一种增殖过度的良性形式。
研究者Bruno表示，罕见的遗传病研究通常会带来意想不到的结果，点状掌跖角皮病病人的表型与寻常性疣的表现相似，我们就推测HPV可能也通过阻断点状掌跖角皮病的发病通路来进行皮肤增殖的诱导，研究发现阐明了EGFR，皮肤癌的标志，也为解释点状掌跖角皮病的发病提供了一些线索。
编译自：<a title="" href="http://www.sciencedaily.com/releases/2012/10/121018123310.htm" target="_blank">Mutation That Causes Skin Hyperproliferation Identified</a>
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<img src="http://www.bioon.com/biology/UploadFiles/201210/2012102012190289.jpg" alt="" width="113" height="149" border="0" />
<a title="" href="http://dx.doi.org/doi:10.1038/ng.2444" target="_blank">doi:10.1038/ng.2444</a>
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<br/><strong>Haploinsufficiency for AAGAB causes clinically heterogeneous forms of punctate palmoplantar keratoderma</strong><br/>
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.
<br/>来源：生物谷
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如今研究者发现了一种促使皮肤层变厚的遗传突变，其主要表现为手掌和足底的皮肤严重加厚，影响患者的正常生活。这种皮肤层变厚的会随着患者的年龄增加而不断增厚，而且会形成较大的皮肤片层，这种皮肤损伤使患者非常疼痛以及虚弱。
来自A*STAR的研究者同英国、日本以及突尼斯等国的研究者联合，发现了这种皮肤病（称为点状掌跖角皮病，punctate PPK）是由于基因AAGAB突变引起的，这种疾病是一种罕见的掌跖角化病，很多患者都受到这种疾病严重的影响。
当前基因突变的发现可以帮助科学家更好地理解该疾病的发病原因，为后续的新型疗法的开发带来了极大帮助，相关研究成果刊登于国际著名杂志<em>Nature Genetics</em>上。
科学家分析了来自苏格兰、日本等国的点状掌跖角皮病的18个家庭的DNA样品，揭示出了编码蛋白p34的基因AAGAB，其可以自皮肤中表达，在控制细胞分裂上扮演着重要角色。AAGAB的剔除可以导致p34的缺失，进而导致皮肤外层细胞的增殖分裂加速。由于增加了生长信号，皮肤外层就会成功产生表皮生长因子（EGFR）。EGFR信号的阻断是异常细胞增殖的一个特点，而且这项研究发现PPK是一种增殖过度的良性形式。
研究者Bruno表示，罕见的遗传病研究通常会带来意想不到的结果，点状掌跖角皮病病人的表型与寻常性疣的表现相似，我们就推测HPV可能也通过阻断点状掌跖角皮病的发病通路来进行皮肤增殖的诱导，研究发现阐明了EGFR，皮肤癌的标志，也为解释点状掌跖角皮病的发病提供了一些线索。
编译自：<a title="" href="http://www.sciencedaily.com/releases/2012/10/121018123310.htm" target="_blank">Mutation That Causes Skin Hyperproliferation Identified</a>
<div id="ztload">
<div></div>
<div>
<div>
<img src="http://www.bioon.com/biology/UploadFiles/201210/2012102012190289.jpg" alt="" width="113" height="149" border="0" />
<a title="" href="http://dx.doi.org/doi:10.1038/ng.2444" target="_blank">doi:10.1038/ng.2444</a>
PMC:
PMID:
</div>
<div>
<br/><strong>Haploinsufficiency for AAGAB causes clinically heterogeneous forms of punctate palmoplantar keratoderma</strong><br/>
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.
<br/>来源：生物谷
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