Ichthyosis in Sjogren-Larsson Syndrome

描述：（逐字）干燥-拉尔森综合征（SLS）是一种遗传性疾病 特征为鱼鳞病、智力低下和痉挛性二瘫或四肢瘫痪。 这种疾病是由脂肪醛脱氢酶基因突变引起的 （β-DH），这导致该酶的活性不足。DHD缺乏症是 与脂肪醛和其他脂质的组织积累有关， 被假设为引起SLS的症状，但致病机制 是未知的。我们研究的长期目标是了解 ESTDDH基因的突变导致SLS的症状，并利用这一知识， 制定有效的治疗方案。 为了了解导致BDH活性缺陷的遗传机制， SLS，我们将描述SLS患者中的某些突变，并研究 选择性剪接基因的功能作用。我们将调查 通过描述异常的 培养的皮肤角质形成细胞和SLS皮肤中的脂质代谢 患者为了了解脂肪醛如何干扰正常表皮细胞， 功能，我们将确定脂肪酸，脂质和蛋白质加合物在SLS 角质形成细胞为了验证新的假设， 角质细胞蛋白有助于鱼鳞病，我们将确定程度 SLS中角质细胞膜中交联蛋白的性质 患者最后，建立了一种用于研究的实验动物模型， 生化发病机制和治疗的SLS，我们将基因工程， DHDH基因敲除小鼠，并使用它来表征生化反应 饮食脂肪改良和药物治疗。这些研究将 提供了关于CD3DH在表皮脂质中的作用的基本信息 代谢，并有望揭示脂肪醛毒性的新机制， SLS.

DESCRIPTION: (Verbatim) Sjogren-Larsson syndrome (SLS) is an inherited disorder characterized by ichthyosis, mental retardation and spastic di- or tetraplegia. The disease is caused by mutations in the gene for fatty aldehyde dehydrogenase (FALDH) which result in deficient activity of this enzyme. FALDH deficiency is associated with tissue accumulation of fatty aldehyde and other lipids, which are hypothesized to cause the symptoms of SLS, but the pathogenic mechanisms are unknown. The long-term goals of our research are to understand how mutations in the FALDH gene lead to symptoms of SLS and use this knowledge to develop effective therapy. To understand the genetic mechanisms leading to deficient FALDH activity in SLS, we will characterize certain mutations in SLS patients and investigate the functional role of alternate splicing of the gene. We will investigate the pathogenesis of the cutaneous disease in SLS by characterizing the abnormal lipid metabolism in cultured skin keratinocytes and in the skin of SLS patients. To understand how fatty aldehyde interferes with normal epidermal function, we will identify fatty aldehyde-lipid and -protein adducts in SLS keratinocytes. To test the novel hypothesis that abnormal crosslinking of corneocyte proteins contributes to the ichthyosis, we will determine the extent and nature of crosslinked proteins in corneocyte cell envelopes from SLS patients. Finally, to develop an experimental animal model for studies of the biochemical pathogenesis and therapy of SLS, we will genetically engineer a FALDH gene knockout mouse and use it to characterize the biochemical response to dietary fat modification and pharmacologic therapy. These studies will provide fundamental information about the role of FALDH in epidermal lipid metabolism and promise to reveal new mechanisms for fatty aldehyde toxicity in SLS.