ICHTHYOSIS IN SJOGREN/LARSSON SYNDROME

干燥/拉尔森综合征中的鱼鳞病

• 批准号: 6171401
• 负责人: WILLIAM B. RIZZO
• 金额: $ 24.36万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-04-10 至 2001-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6171401
• 关键词: aldehyde dehydrogenases; biopsy; clinical research; congenital ichthyosis; disease /disorder etiology; enzyme activity; enzyme deficiency; gene expression; genetic disorder; genetic transcription; human subject; mental retardation; molecular pathology; spastic paralysis; tissue /cell culture

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.

描述：（改编自申请人的摘要）- Sjogren-Larsson 综合征（SLS）是一种遗传性神经皮肤疾病，其特征为 鱼鳞病、智力低下和痉挛。 该病源于 脂肪醛脱氢酶（FALDH）基因突变，导致 这种酶的活性不足以及脂肪醇的积累 组织。 研究的长期目标是了解 SLS 的发病机制并开发针对该疾病的有效治疗方法。 识别 SLS 中的遗传缺陷并揭示影响的氨基酸 对于 FALDH 的催化活性至关重要，申请人将调查 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进行 DNA 测序。 已确定的突变将在哺乳动物中进行测试 表达系统以确认它们负责还原酶 活动。 确定 SLS 的表型变异是否由遗传引起 FALDH 的异质性，申请人将关联临床表型 患者的生化异常，包括残留 培养的成纤维细胞和角质细胞、细胞脂肪中的酶活性 酒精储存，血浆和红细胞中脂肪醇的积累，以及， 对于那些纯合子患者，FALDH 突变的位置。 为了更好地了解 SLS 的发病机制，他们将比较 培养的皮肤活检中 FALDH 的转录和表达 来自 SLS 患者和正常对照的角质形成细胞和成纤维细胞。 由可变剪接产生的 FALDH 转录本将被定义，它们的 表皮中细胞的位置和培养物中的相对丰度 将确定角质形成细胞，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角质形成细胞的能力 FALDH 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 造成皮肤症状。 这些知识对于 开发针对这种疾病的有效治疗方法。