【作者】 顾卫红；

【导师】 沈岩； 钟南；

【作者基本信息】 中国协和医科大学 ， 生物化学与分子生物学， 2004， 博士

【摘要】 神经元蜡样脂质褐素沉积病(Neuronal ceroid-lipofuscinoses，NCLs)是一组遗传性神经系统变性疾病，具有高度临床变异和遗传异质性。根据发病年龄和病程将NCL分为5种临床类型，即婴儿型(INCL)、晚期婴儿型(LINCL)、青少年型(JNCL)、成人型(ANCL)和Northern癫痫型(NE)。其遗传模式多为常染色体隐性遗传，成人型可表现为常染色体显性遗传。由于对这类疾病的发病机制缺乏足够的认识，因此在二十世纪九十年代以前人们对它的研究仅停留在临床和病理水平。随着分子生物学的发展，人们采用定位克隆的研究策略，绕开表现型与基因之间一系列的作用环节，不断发现这类疾病的遗传学病因，并以此对其进行了更为科学准确的基因分型。目前已经定位6个常染色体隐性遗传NCL的致病基因(CLN1、CLN2、CLN3、CLN5、CLN6和CLN8)，其中CLN1编码棕榈酰蛋白硫脂酶1，CLN2编码三肽基肽酶1，CLN3，CLN5，CLN6和CLN8编码4种跨膜蛋白(功能未知)。 在本研究中，我们对一个姓氏为Parry的成人型常染色体显性遗传NCL家系进行致病基因定位，此家系中7代共22人发病(男性8人，女性14人)，外显完全，患者大多于31岁左右发病，平均病程为7年，表现为癫痫，肌阵挛，痴呆，小脑共济失调，原发性高血压，家族内表型变异很少。病理显示：大脑神经元和胶质细胞内大量自发荧光的脂色素沉积，超微结构为颗粒样小体，黑质神经元和小脑蒲肯野细胞严重丢失。由于目前尚无对此型NCL基因定位报道，所以我们采用全基因组扫描、精细定位、两点连锁分析一系列方法将其致病基因定位在6号染色体6q23.2的D6S262～D6S975之间3.18 cM的区间，在D6S472获得最大LOD值，Zmax=3.38(θ=0.00)，单倍型分析显示与疾病表型紧密连锁的核心单倍型为D6S262-D6S457-D6S472-D6S413。此结果为下一步致病基因的克隆奠定了基础，并对OMIM数据库中收录的另3个Parry型NCL家系的研究具有重要的参考价值。更多还原

【Abstract】 The neuronal ceroid-lipofuscinoses(NCLs) are a large group of progressive neurodegenerative diseases with high phenotypic and genotypic heterogeneity. NCLs have originally been classified clinically by age of onset and clinical course: infantile form (INCL), late infantile form (LINCL), juvenile form (JNCL), adult form (ANCL, Kufs disease) and Northern Epilepsy (NE). In most cases, NCLs are inherited in an autosomal recessive manner, although some adult form cases are inherited in an autosomal dominant manner. Because of poor understanding of the pathogenesis, the research on this group of diseases had been limited before 1990’s. Along with the development of molecular biology, positional cloning strategy was used to reveal the genetic basis of the diseases with unknown biochemical defects. So far six genes associated with NCL have been isolated and characterized: CLN1, CLN2, CLN3, CLN5, CLN6 and CLN8. The CLN1 gene encodes palmitoyl protein thioesterase 1 (PPT1) while the CLN2 gene encodes tripeptidyl peptidase 1 (TPP1), CLN3, CLN5, CLN6 and CLN8, which encode novel transmembrane proteins, mutation in any one of these genes results in phenotype of NCL-disease. However, the gene responsible for adult-form NCL has not yet been identified.In the present study, we describe an US family named Parry with Kufs disease, which was inherited as an apparently autosomal dominant trait with full penetrance.Twenty-two individuals (eight men, fourteen women) have been affected over seven generations. The clinical course was strikingly consistent with onset at around 31 years of age and an average duration of seven years. Affected更多还原