A mutation in the cathepsin D gene (CTSD) in American Bulldogs with neuronal ceroid lipofuscinosis
A mutation in the cathepsin D gene (CTSD) in American Bulldogs with neuronal ceroid lipofuscinosis
复制标题
DOI：
10.1016/j.ymgme.2005.11.005
复制
发表时间：
2006-04-01
影响因子：
3.8
通讯作者：
Johnson, GS
中科院分区：
文献类型：
--
作者：
Awano, T;Katz, ML;Johnson, GS
我们从患有神经元蜡样质脂褐质沉积症（NCL）的美国斗牛犬中获得了DNA、大脑和眼睛。NCL的诊断通过检测整个脑中的神经元内、视网膜神经节细胞中和沿视网膜的沿着外界膜的自发荧光细胞质内含物来证实。电镜下可见包涵体周围有粗糙的颗粒状基质，周围有轮廓清晰的球形结构，视网膜外界膜附近的包涵体位于感光细胞内，主要是视锥细胞。受影响的美国斗牛犬是组织蛋白酶D基因（CTSD）中G至A转变的A等位基因纯合型，该基因预测甲硫氨酸-199转化为所有异亮氨酸。在131只随机选择的代表108个品种的犬的DNA样本中，只有G等位基因被检测到，但在123只基因型美国斗牛犬中，A等位基因的频率为0.28。对99只美国斗牛犬系谱的传播分析表明，来自与CTSD无关的任何突变的等位基因与狗的系谱和表型一致的概率小于10（-7）。从受影响的狗的脑样品中发现对照犬脑组织蛋白酶D特异性酶活性的36%，而其他15种溶酶体酶的特异性酶活性不变或增加。与先前描述的完全缺乏组织蛋白酶D活性的小鼠和绵羊中的NCL相比，美国斗牛犬中的NCL的临床过程不太严重，并且更接近于许多人类NCL。(c)2005年爱思唯尔公司All rights reserved.
We obtained DNA, brains, and eyes from American Bulldogs with neurodegeneration due to neuronal ceroid lipofuscinosis (NCL). The diagnosis of NCL was confirmed by detection of autofluorescent cytoplasmic inclusions within neurons throughout the brains, in retinal ganglion cells, and along outer limiting membranes of the retinas. Electron microscopy revealed that the inclusions had coarsely granular matrices Surrounding well-delineated spherical structures and that the inclusions near the retinal outer limiting membranes were within photoreceptor cells, mostly cones. Affected American Bulldogs were homozygous for the A allele of a G to A transition ill the cathepsin D gene (CTSD), which predicts the conversion of methionine-199 to all isoleucine. Only the G allele was detected in DNA samples from 131 randomly selected dogs representing 108 breeds other than American Bulldog; however, the A allele had a frequency of 0.28 among 123 genotyped American Bulldogs. Transmission analysis in a 99 dog pedigree of American Bulldogs indicated a probability of less than 10(-7) that alleles from any mutation unlinked to CTSD would be concordant with the pedigree and phenotypes of the dogs. Brain samples from affected dogs had 36% of the cathepsin D-specific enzymatic activity found in control dog brains; whereas, specific enzymatic activities of 15 other lysosomal enzymes were unchanged or increased. Compared to previously described NCLs in mice and sheep that completely lack cathepsin D activity, the clinical course of NCL in the American Bulldogs was less severe and more closely resembled that of many human NCLs. (c) 2005 Elsevier Inc. All rights reserved.