ICHTHYOSIS IN SJOGREN/LARSSON SYNDROME

描述：(改编自申请者的摘要)-The Sjogren-Larsson 综合征(SLS)是一种遗传性神经皮肤病，其特征是 鱼鳞病、智力低下和痉挛。这种疾病的起因是 脂肪醛脱氢酶(FALDH)基因突变 这种酶的活性不足和脂肪醇在体内的积累 纸巾。这项研究的长期目标是了解 系统性红斑狼疮的发病机制和开发有效的治疗方法。 识别系统性红斑狼疮的遗传缺陷并发现 对于FALDH的催化活性至关重要，申请者将调查 一大组无关系统性红斑狼疮突变的性质和分布 病人。突变分析将通过外显子筛选和直接 DNA测序。已确定的突变将在哺乳动物身上进行测试 表达系统来确认它们对酶的还原负责 活动。 确定系统性红斑狼疮的表型变异是否源于遗传 FALDH的异质性，申请者将与临床表型相关 患者的生化异常，包括残留物 培养的成纤维细胞和角质形成细胞的酶活性，细胞脂肪 酒精储存，血浆和红细胞中脂肪酒精的积累，以及， 对于那些纯合子的患者，FALDH突变的位置。 为了更好地了解SLS的发病机制，他们将比较 培养的皮肤活检组织中FALDH的转录和表达 角质形成细胞、SLS患者和正常对照的成纤维细胞。 将定义由选择性剪接产生的FALDH转录本，其 细胞在表皮中的定位和培养的相对丰度 角质形成细胞将被确定，其功能将被研究。 使用转染法。此外，皮肤等效培养将是 用来检测培养的SLS角质形成细胞模拟体内的能力 FALDH的表达及相关的表皮异常。 这些研究将确定SLS的遗传基础，并提供新的 对分子和生化异常的理解 对皮肤症状负责。这方面的知识对 开发有效的治疗方法来治疗这种疾病。

DESCRIPTION: (Adapted from the applicant's abstract) - The Sjogren-Larsson syndrome (SLS) is an inherited neurocutaneous disorder characterized by ichthyosis, mental retardation, and spasticity. The disease arises from mutations in the gene for fatty aldehyde dehydrogenase (FALDH) which result in deficient activity of this enzyme and accumulation of fatty alcohol in tissues. The long-term goal of the research is to understand the pathogenesis of SLS and develop effective therapy for this disease. To identify the genetic defects in SLS and uncover amino acids that are critical for catalytic activity of FALDH, the applicants will investigate the nature and distribution of mutations in a large group of unrelated SLS patients. Mutation analysis will be performed by exon screening and direct DNA sequencing. Identified mutations will be tested in a mammalian expression system to confirm that they are responsible for reduced enzyme activity. To determine whether phenotypic variation in SLS arises from genetic heterogeneity in FALDH, the applicants will correlate the clinical phenotype with the biochemical abnormalities in patients, including the residual enzymatic activity in cultured fibroblasts and keratinocytes, cellular fatty alcohol storage, fatty alcohol accumulation in plasma and erythrocytes, and, for those patients who are homozygous, the location of mutations in FALDH. To understand better the pathogenesis of SLS, they will compare the transcription and expression of FALDH in skin biopsies, cultured keratinocytes, and fibroblasts from SLS patients, and normal controls. FALDH transcripts arising from alternative splicing will be defined, their cellular location in the epidermis and relative abundance in cultured keratinocytes will be determined, and their function will be investigated using transfection assays. In addition skin equivalent cultures will be used to test the ability of cultured SLS keratinocytes to mimic the in vivo expression of FALDH and associated epidermal abnormalities. These studies will define the genetic basis for SLS and provide new understanding of the molecular and biochemical abnormalities that are responsible for cutaneous symptoms. This knowledge is critical for developing effective therapeutic approaches to this disease.