ICHTHYOSIS IN SJOGREN/LARSSON SYNDROME

描述：（改编自申请人的摘要）- The Sjogren-Larsson 综合征（SLS）是一种遗传性神经皮肤疾病， 鱼鳞病、智力迟钝和痉挛状态。 这种疾病源于 脂肪醛脱氢酶（FATIGUE DEHYDROGENERATION）基因突变， 由于这种酶活性不足和脂肪醇在 组织中 这项研究的长期目标是了解 研究SLS的发病机制，并开发有效的治疗方法。 为了确定SLS中的遗传缺陷，并揭示与SLS相关的氨基酸， 关键的催化活性，申请人将调查 在一大群不相关的SLS中突变的性质和分布 患者 突变分析将通过外显子筛选和直接测序进行。 DNA测序 将在哺乳动物中检测鉴定的突变 表达系统，以确认它们负责还原酶 活动 为了确定SLS的表型变异是否来自遗传因素， 如果存在CMDH的异质性，则申请人将临床表型与 与患者的生化异常，包括残留的 在培养的成纤维细胞和角质形成细胞、细胞脂肪 酒精储存，血浆和红细胞中的脂肪醇积累，以及， 对于那些纯合子患者，则是CD 3DH中突变的位置。 为了更好地了解SLS的发病机制，他们将比较 在皮肤活检组织中，培养的 角化细胞和成纤维细胞，来自SLS患者和正常对照。 将定义由选择性剪接产生的CD 3DH转录物，其 细胞在表皮中的位置和培养的 确定角质形成细胞，并研究其功能 使用转染测定。 此外，皮肤等效培养物将 用于测试培养的SLS角质形成细胞模拟体内 ESTDDH的表达和相关的表皮异常。 这些研究将确定SLS的遗传基础，并提供新的 了解分子和生化异常 导致皮肤症状。 这些知识对于 开发针对这种疾病的有效治疗方法。

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.