Molecular Pathogenesis of Genetic and Inherited Diseases Premature Terminal Differentiation and a Reduction in Specific Proteases Associated with Loss of ABCA12 in Harlequin Ichthyosis
Molecular Pathogenesis of Genetic and Inherited Diseases Premature Terminal Differentiation and a Reduction in Specific Proteases Associated with Loss of ABCA12 in Harlequin Ichthyosis
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遗传性疾病的分子发病机制 丑角鱼鳞病中与 ABCA12 缺失相关的过早终末分化和特异性蛋白酶的减少
DOI：
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发表时间：
2009
期刊：
影响因子：
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通讯作者：
D. Kelsell
中科院分区：
文献类型：
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作者：
Anna Thomas;D. Tattersall;E. Norgett;E. O’Toole;D. Kelsell
皮肤的主要功能之一是形成防御屏障，防止外部感染和水分流失。屏障功能的破坏是隐性先天性鱼鳞病——小丑鱼鳞病（HI）最严重和最致命的原因。HI与编码ABC转运蛋白ABCA12的基因突变有关。我们研究了HI表皮中与异常表皮分化和屏障形成相关的形态学和生化改变。在三维器官型共培养（OTCC）系统中，利用人角质形成细胞逆转录病毒转导靶向ABCA12的shRNA，建立了HI皮肤的体外模型。ABCA12表达的显著减少对角质细胞分化和形态产生了与HI皮肤相似的显著影响，包括更厚的表皮和非极性脂质减少的异常脂质含量。如在HI表皮中所见，在abca12消融的OTCC系统中，通常在晚期分化中表达的蛋白质高度失调。这些蛋白在基底层和棘层中表达，表明了过早的终末分化表型。在HI表皮和OTCC模型中，蛋白酶kallikrein 5和cathepsin D的表达均显著降低。这些数据表明，ABCA12是调节角质形成细胞分化和转运与脱屑相关的特定蛋白酶的关键分子。（美国病理学杂志2009,174:970-978;DOI: 10.2353/ajpath.2009.080860）丑角鱼鳞病（HI; MIM 242500）是隐性先天性鱼鳞病中最严重和经常致命的形式。出生时患有HI的婴儿皮肤坚硬、厚实，覆盖了大部分身体。皮肤形成巨大的菱形板，类似于装甲，由深红色的裂缝分开，限制了活动。这些皮肤异常也会影响眼睑和嘴唇的形状，分别引起外翻和外翻。HI患者也可能因为子宫内的皮肤收缩而导致手指和脚趾畸形或自动截肢。由于皮肤屏障功能受损，新生儿难以控制失水、调节体温，更容易感染并有喂养困难。此外，紧绷的皮肤会导致呼吸困难，导致呼吸衰竭。从我们70多个不相关家庭的队列数据来看，45%的hi感染新生儿在出生后不久死亡（如果不是死胎）。6个月以后的疾病类似于非大疱性先天性鱼鳞状红皮病。然而，HI患者的皮肤屏障仍然严重受损，他们总是有热调节问题，表皮水分流失增加，微生物感染的风险更大。HI的缺陷基因是ABCA12，是三磷酸腺苷（ATP）结合盒（ABC）活性转运蛋白超家族的成员。ABCA12突变是迄今为止分析的所有HI病例的原因，大多数突变是无义替换或移码。ABCA12定位于正常表皮角质形成细胞的板层颗粒（LG）。ABCA12蛋白在LG脂质转运中的确切作用尚不清楚，但假设ABCA12转运葡萄糖-
One of the primary functions of skin is to form a defensive barrier against external infections and water loss. Disrupted barrier function underlies the most severe and often lethal form of recessive congenital ichthyosis, harlequin ichthyosis (HI). HI is associated with mutations in the gene that encodes the ABC transporter protein, ABCA12. We have investigated the morphological and biochemical alterations associated with abnormal epidermal differentiation and barrier formation in HI epidermis. An in vitro model of HI skin using human keratinocytes retrovirally transduced with shRNA targeting ABCA12 in a three-dimensional , organotypic co-culture (OTCC) system has also been developed. A robust reduction in ABCA12 expression had a dramatic effect on keratinocyte differentiation and morphology comparable with that observed in HI skin, including a thicker epidermis and abnormal lipid content with a reduction in nonpolar lipids. As seen in HI epidermis, proteins that are normally expressed in late differentiation were highly dysregulated in the ABCA12-ablated OTCC system. These proteins were expressed in the stratum basale and also in the stratum spinosum, indicative of a premature terminal differentiation phenotype. Expression of the proteases kallikrein 5 and cathepsin D was dramatically reduced in both HI epidermis and the OTCC model. These data suggest that ABCA12 is a key molecule in regulating keratinocyte differentiation and transporting specific proteases associated with desquamation. (Am J Pathol 2009, 174:970–978; DOI: 10.2353/ajpath.2009.080860) Harlequin ichthyosis (HI; MIM 242500) is the most severe and often lethal form of recessive congenital ichthyosis. Infants born with HI have hard, thick skin covering most of their body. The skin forms large diamond-shaped plates resembling armor plating separated by deep red fissures, which restrict movement. These skin abnormalities also affect the shape of the eyelids and lips, causing ectropion and eclabion, respectively. HI sufferers can also have malformations or autoamputation of the fingers and toes because of constricting bands of skin in utero. Because of the impaired barrier function of the skin, neonates struggle to control water loss, regulate temperature, and are more susceptible to infection and have feeding difficulties. In addition, the tightened skin produced can cause breathing difficulties leading to respiratory failure. From our cohort data of more than 70 unrelated families, 45% of HI-affected neonates die soon after birth (if not still-born). Disease from 6 months onwards resembles a nonbullous congenital ichthyosiform erythroderma. However, the skin barrier still remains severely compromised in HI patients, and they will always have problems with thermal regulation, have increased trans-epidermal water loss, and be at a greater risk of microbial infection. The gene defective in HI is ABCA12, a member of the adenosine triphosphate (ATP)-binding cassette (ABC) superfamily of active transporters. ABCA12 mutations are responsible for all HI cases analyzed to date with the majority of mutations being either nonsense substitution or frameshift. ABCA12 localizes to lamellar granules (LG) in normal epidermal keratinocytes. The exact role of the ABCA12 protein in LG lipid transport is unknown, but it is hypothesized that ABCA12 transports glucosyl-
影响因子：
6.5
作者：
Ishida-Yamamoto, A;Deraison, C;Hovnanian, A
通讯作者：
Hovnanian, A
影响因子：
9.8
作者：
D. Kelsell;E. Norgett;Harriet C Unsworth;M. Teh;T. Cullup;C. Mein;P. Dopping-Hepenstal;B. Dale;G. Tadini;P. Fleckman;K. Stephens;V. Sybert;S. Mallory;B. North;D. Witt;E. Sprecher;A. Taylor;A. Ilchyshyn;C. Kennedy;H. Goodyear;C. Moss;D. Paige;J. Harper;B. Young;I. Leigh;R. Eady;E. O’Toole
通讯作者：
D. Kelsell;E. Norgett;Harriet C Unsworth;M. Teh;T. Cullup;C. Mein;P. Dopping-Hepenstal;B. Dale;G. Tadini;P. Fleckman;K. Stephens;V. Sybert;S. Mallory;B. North;D. Witt;E. Sprecher;A. Taylor;A. Ilchyshyn;C. Kennedy;H. Goodyear;C. Moss;D. Paige;J. Harper;B. Young;I. Leigh;R. Eady;E. O’Toole
影响因子：
6.5
作者：
DALE, BA;HOLBROOK, KA;SYBERT, VP
通讯作者：
SYBERT, VP