Fatal cardiac arrhythmia and long-QT syndrome in a new form of congenital generalized lipodystrophy with muscle rippling (CGL4) due to PTRF-CAVIN mutations.
Fatal cardiac arrhythmia and long-QT syndrome in a new form of congenital generalized lipodystrophy with muscle rippling (CGL4) due to PTRF-CAVIN mutations.
复制标题
DOI：
10.1371/journal.pgen.1000874
复制
发表时间：
2010-03-12
期刊：
影响因子：
4.5
通讯作者：
Schuelke M
中科院分区：
文献类型：
--
作者：
Rajab A;Straub V;McCann LJ;Seelow D;Varon R;Barresi R;Schulze A;Lucke B;Lützkendorf S;Karbasiyan M;Bachmann S;Spuler S;Schuelke M
我们调查了8个家族与一种新的亚型先天性全身性脂肪营养不良（CGL 4），其中5名成员死于心脏性猝死在他们的青少年时期。心电图检查显示了长QT综合征、心动过缓以及室上性和室性心动过速的特征。进一步的症状包括肌病伴肌肉波纹、骨骼肌和平滑肌肥大，导致部分儿童胃肠动力受损和肥厚性幽门狭窄。此外，我们还发现骨形成受损，伴有骨质减少、骨质疏松和寰枢椎不稳。纯合性定位的基因在2 Mbp的17号染色体。用GeneDistiller对74个候选基因在肌肉和脂肪细胞中的高表达进行优先排序，表明PTRF-CAVIN（聚合酶I和转录物释放因子/Cavin）是导致检测到纯合突变（c.160delG，c.362dupT）的最可能的候选基因。PTRF-CAVIN是小窝生物发生所必需的。这些富含胆固醇的质膜囊泡参与信号转导和囊泡运输，主要存在于脂肪细胞、肌细胞和成骨细胞上。PTRF-CAVIN的缺乏不影响其结合伴侣小窝蛋白-1和小窝蛋白-3的丰度。然而，在患者成纤维细胞中，小窝蛋白-1未能定位于细胞表面，电子显微镜显示小窝减少到不到3%。全长PTRF-CAVIN的转染重新建立了小窝的存在。通过原子力显微镜（AFM）结合荧光成像证实小窝的损失。因此，PTRF-CAVIN缺陷呈现出由典型的功能性小窝缺乏引起的表型谱。全身性脂肪代谢障碍患者明显缺乏体脂。已经描述了几种基因缺陷阻碍脂肪合成和脂肪细胞成熟。在这里，我们报告了一个新的基因突变，称为PTRF-CAVIN，导致先天性全身性脂肪营养不良4型（CGL 4），这是额外的肌肉疾病相关。患者的肌肉很大但很弱，表现出一种不自主的、滚动的收缩模式，称为“波纹”。其他症状包括危及生命的心律失常和骨形成障碍。我们在7名患者的基因组中搜索了共享片段，并在17号染色体上找到了负责基因PTRF-CAVIN。这个基因对于小窝（拉丁语中的“小洞穴”）的形成至关重要。这些细胞膜的小凹痕存在于肌肉、骨骼、脂肪和免疫细胞的表面上，并促进细胞与细胞的通讯和从细胞外空间吸收物质。患者缺乏超过97%的小窝，人工将正确的基因插入患者皮肤细胞导致小窝的重现。由于心律失常是一种严重且可能危及生命的疾病，因此应通过ECG密切监测CGL 4患者，并在必要时安装植入式起搏器和心律转复除颤器（ICD）装置。
We investigated eight families with a novel subtype of congenital generalized lipodystrophy (CGL4) of whom five members had died from sudden cardiac death during their teenage years. ECG studies revealed features of long-QT syndrome, bradycardia, as well as supraventricular and ventricular tachycardias. Further symptoms comprised myopathy with muscle rippling, skeletal as well as smooth-muscle hypertrophy, leading to impaired gastrointestinal motility and hypertrophic pyloric stenosis in some children. Additionally, we found impaired bone formation with osteopenia, osteoporosis, and atlanto-axial instability. Homozygosity mapping located the gene within 2 Mbp on chromosome 17. Prioritization of 74 candidate genes with GeneDistiller for high expression in muscle and adipocytes suggested PTRF-CAVIN (Polymerase I and transcript release factor/Cavin) as the most probable candidate leading to the detection of homozygous mutations (c.160delG, c.362dupT). PTRF-CAVIN is essential for caveolae biogenesis. These cholesterol-rich plasmalemmal vesicles are involved in signal-transduction and vesicular trafficking and reside primarily on adipocytes, myocytes, and osteoblasts. Absence of PTRF-CAVIN did not influence abundance of its binding partner caveolin-1 and caveolin-3. In patient fibroblasts, however, caveolin-1 failed to localize toward the cell surface and electron microscopy revealed reduction of caveolae to less than 3%. Transfection of full-length PTRF-CAVIN reestablished the presence of caveolae. The loss of caveolae was confirmed by Atomic Force Microscopy (AFM) in combination with fluorescent imaging. PTRF-CAVIN deficiency thus presents the phenotypic spectrum caused by a quintessential lack of functional caveolae. Patients with generalized lipodystrophy have a marked lack of body fat. Several gene defects have been described that impede fat synthesis and maturation of fat cells. Here we report on mutations in a novel gene, called PTRF-CAVIN, causing congenital generalized lipodystrophy type 4 (CGL4) that is additionally associated with muscle disease. Patients' muscles are large but weak and show an involuntary, rolling contraction pattern called “rippling.” Further symptoms comprise life-threatening cardiac arrhythmias and a disorder of bone formation. We searched for shared segments in the genome of seven patients and found the responsible gene, called PTRF-CAVIN, on chromosome 17. This gene is crucial for caveolae (latin for “small caves”) formation. These small indentations of the cell membrane are found on the surface of muscle, bone, fat, and immune cells and facilitate cell-to-cell communication and the absorption of substances from the extracellular space. Patients lack more than 97% of caveolae and artificial insertion of the correct gene into patient skin cells led to the reappearance of caveolae. As cardiac arrhythmia is a severe and potentially life-threatening condition, patients with CGL4 should be closely monitored by ECG and, if necessary, fitted with an implanted pacemaker and cardioverter defibrillator (ICD) device.
登录
查看更多内容
影响因子：
5.8
作者：
Kim, C. A.;Delepine, Marc;Magre, Jocelyne
通讯作者：
Magre, Jocelyne
影响因子：
5.5
作者：
Frank, Philippe G.;Pavlides, Stephanos;Lisanti, Michael P.
通讯作者：
Lisanti, Michael P.
影响因子：
5.3
作者：
Hartung, Anke;Bitton-Worms, Keren;Knaus, Petra
通讯作者：
Knaus, Petra
影响因子：
4.3
作者：
Medina, Freddy A.;Williams, Terence M.;Lisanti, Michael P.
通讯作者：
Lisanti, Michael P.
影响因子：
29
作者：
Liu L;Brown D;McKee M;Lebrasseur NK;Yang D;Albrecht KH;Ravid K;Pilch PF
通讯作者：
Pilch PF