Molecular genetics of palmitoyl protein thioesterase deficiency in the US
Molecular genetics of palmitoyl protein thioesterase deficiency in the US
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DOI：
10.1172/jci3112
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发表时间：
1998-07-15
影响因子：
15.9
通讯作者：
Hofmann, SL
中科院分区：
文献类型：
--
作者：
Das, AK;Becerra, CHR;Hofmann, SL
最近发现，一种新描述的溶酶体酶棕榈酰蛋白硫酯酶（PPT）的突变导致芬兰流行的常染色体隐性遗传神经系统疾病婴儿神经元蜡样脂褐质沉积症。这种疾病会导致失明、运动和认知能力下降以及癫痫发作。在脑和其他组织中发现特征性包涵体（颗粒状嗜锇沉积物[GROD]）。绝大多数芬兰病例是严重影响PPT酶活性的错义突变（R122W）的纯合子，并且芬兰儿童的临床过程是一致的快速进展和致命的。以及在更广泛人群中PPT缺乏症受试者的分子遗传学特征，我们收集了来自美国和加拿大的受试者的血液样本，这些受试者代表32个不相关的神经元蜡样质脂褐质沉积症家族，这些家族在形态学上有GROD记录。我们测量PPT活性并筛选PPT基因的编码区突变。在29个家庭中，发现PPT缺乏症是神经退行性疾病的原因，在58个PPT等位基因中有57个发现了突变。一个无义突变（R151X）占等位基因的40%，并与纯合状态下的严重疾病相关。第二个突变（T75P）占等位基因的13%，与晚发和长期的临床过程。总共发现了19种不同的突变，导致比以前在芬兰人群中看到的更广泛的临床表现。症状首先出现在3个月至9岁的年龄范围内，大约一半的受试者已经存活到生命的第二个甚至第三个十年。
Mutations in a newly described lysosomal enzyme, palmitoyl-protein thioesterase (PPT), were recently shown to be responsible for an autosomal recessive neurological disorder prevalent in Finland, infantile neuronal ceroid lipofuscinosis. The disease results in blindness, motor and cognitive deterioration, and seizures. Characteristic inclusion bodies (granular osmiophilic deposits [GROD]) are found in the brain and other tissues. The vast majority of Finnish cases are homozygous for a missense mutation (R122W) that severely affects PPT enzyme activity, and the clinical course in Finnish children is uniformly rapidly progressive and fatal.To define the clinical, biochemical; and molecular genetic characteristics of subjects with PPT deficiency in a broader population, we collected blood samples from U.S. and Canadian subjects representing 32 unrelated families with neuronal ceroid lipofuscinosis who had GROD documented morphologically. We measured PPT activity and screened the coding region of the PPT gene for mutations. In 29 of the families, PPT deficiency was found to be responsible for the neurodegenerative disorder, and mutations were identified in 57 out of 58 PPT alleles. One nonsense mutation (R151X) accounted for 40% of the alleles and was associated with severe disease in the homozygous state. A second mutation (T75P) accounted for 13% of the alleles and was associated with a late onset and protracted clinical course. A total of 19 different mutations were found, resulting in a broader spectrum of clinical presentations than previously seen in the Finnish population. Symptoms first appeared at ages ranging from 3 mo to 9 yr, and about half of the subjects have survived into the second or even third decades of life.