Epidermal expression of the truncated prelamin A causing Hutchinson-Gilford progeria syndrome: effects on keratinocytes, hair and skin.
Epidermal expression of the truncated prelamin A causing Hutchinson-Gilford progeria syndrome: effects on keratinocytes, hair and skin.
复制标题
导致 Hutchinson-Gilford 早衰综合征的截短的 prelamin A 的表皮表达：对角质形成细胞、头发和皮肤的影响。
DOI：
10.1093/hmg/ddn136
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发表时间：
2008
影响因子：
3.5
通讯作者：
Worman,HowardJ
中科院分区：
文献类型：
--
作者：
Wang,Yuexia;Panteleyev,AndreyA;Owens,DavidM;Djabali,Karima;Stewart,ColinL;Worman,HowardJ
哈钦森-吉尔福德早衰综合症 (HGPS) 是一种由编码 A 型核纤层蛋白的 LMNA 点突变引起的加速衰老疾病。 LMNA 中的突变激活了一个隐秘的剪接供体位点，导致表达一种截短的异戊二烯化前核纤层蛋白 A，称为早衰蛋白。早老蛋白的表达导致核形态的改变，这可能是 HGPS 病理学的基础。我们生成了在角蛋白 14 启动子控制下在表皮中表达早老素的转基因小鼠。小鼠皮肤角质形成细胞核形态严重异常，包括表达野生型人核纤层蛋白A的转基因小鼠中不存在的核膜分叶和核圆形度降低。与表达野生型人核纤层蛋白A的转基因小鼠相比，从这些小鼠中分离的原代角质形成细胞具有更高频率的形状异常的细胞核。用法呢基转移酶抑制剂治疗显着改善了核形状异常，并诱导表达早衰蛋白的原代角质形成细胞中核内病灶的形成。类似地，选择具有正常核形态的细胞表达早老蛋白的培养角质形成细胞的自发永生化。尽管角质形成细胞核的形态发生变化，但表皮表达早老素的小鼠毛发生长和伤口愈合正常。即使在与Lmnanull小鼠杂交以减少或消除正常A型核纤层蛋白的表达后，毛发和皮肤厚度仍正常。尽管早老蛋白会诱导角质形成细胞核形态的显着改变，而这种改变可以通过抑制法尼基转移酶来逆转，但表皮表达不会导致脱发或其他通常在患有 HGPS 的人类受试者中看到的皮肤异常。
Hutchinson–Gilford progeria syndrome (HGPS) is an accelerated aging disorder caused by point mutation inLMNAencoding A-type nuclear lamins. The mutations inLMNAactivate a cryptic splice donor site, resulting in expression of a truncated, prenylated prelamin A called progerin. Expression of progerin leads to alterations in nuclear morphology, which may underlie pathology in HGPS. We generated transgenic mice expressing progerin in epidermis under control of a keratin 14 promoter. The mice had severe abnormalities in morphology of skin keratinocyte nuclei, including nuclear envelope lobulation and decreased nuclear circularity not present in transgenic mice expressing wild-type human lamin A. Primary keratinocytes isolated from these mice had a higher frequency of nuclei with abnormal shape compared to those from transgenic mice expressing wild-type human lamin A. Treatment with a farnesyltransferase inhibitor significantly improved nuclear shape abnormalities and induced the formation of intranuclear foci in the primary keratinocytes expressing progerin. Similarly, spontaneous immortalization of progerin-expressing cultured keratinocytes selected for cells with normal nuclear morphology. Despite morphological alterations in keratinocyte nuclei, mice expressing progerin in epidermis had normal hair grown and wound healing. Hair and skin thickness were normal even after crossing toLmnanull mice to reduce or eliminate expression of normal A-type lamins. Although progerin induces significant alterations in keratinocyte nuclear morphology that are reversed by inhibition of farnesyltransferasae, epidermal expression does not lead to alopecia or other skin abnormalities typically seen in human subjects with HGPS.