Yang Zhao, Funke Birgit H, Cripe Linda H, Vick G Wesley, Mancini-Dinardo Debora, Peña Liana S, Kanter Ronald J, Wong Brenda, Westerfield Brandy H, Varela Jaquelin J, Fan Yuxin, Towbin Jeffrey A, Vatta Matteo
Department of Pediatrics, Baylor College of Medicine, Texas Children's Hospital, Houston, USA.
Circ Cardiovasc Genet. 2010 Apr;3(2):129-37. doi: 10.1161/CIRCGENETICS.109.901785. Epub 2010 Feb 20.
Danon disease is an X-linked dominant disorder characterized by the clinical triad of hypertrophic cardiomyopathy, skeletal myopathy, and variable mental retardation. Pathologically, autophagic vacuoles are noted in both skeletal and cardiac muscle. It exhibits an X-linked dominant mode of inheritance, and male carriers are severely affected, whereas female carriers develop milder and later-onset cardiac symptoms. Danon disease has been associated with mutations in the lysosome-associated membrane glycoprotein 2 (LAMP2) gene located at Xq24, typically resulting in splicing defects or protein truncation affecting the LAMP2. Because of its rarity, the full spectrum of genetic mutation resulting in Danon disease has not been elucidated.
We analyzed 3 male cases with clinical and pathological findings consistent with Danon disease. Comprehensive mutational analysis failed to yield detectable products for selected LAMP2 exons, and genomic DNA deletion was suspected. Genomic junction fragment polymerase chain reaction analysis in case 1 identified a novel Alu-mediated 34-kb microdeletion encompassing the entire 5'-untranslated region and exon 1 of LAMP2. In case 2 and 3, junctional polymerase chain reaction and Southern blot analyses mapped the breakpoint to an MIRb and (TA)(n) simple repeats present in intron 3, which determined a 64-kb and a 58-kb deletion, respectively, thereby ablating exons 4 to 10. Western blot analysis confirmed the absence of LAMP2 in protein extract from lymphocytes of index case 2.
This article is the first report of Danon disease caused by microdeletions at Xq24, which functionally ablate LAMP2. The microdeletion mechanism appears to involve 1 Alu-mediated unequal recombination and 2 chromosomal breakage points involving TA-rich repeat sequences.
丹农病是一种X连锁显性疾病，其临床特征为肥厚型心肌病、骨骼肌病和不同程度的智力发育迟缓三联征。病理上，在骨骼肌和心肌中均可见自噬空泡。它呈现X连锁显性遗传模式，男性携带者受严重影响，而女性携带者则出现较轻且发病较晚的心脏症状。丹农病与位于Xq24的溶酶体相关膜糖蛋白2（LAMP2）基因突变有关，通常导致影响LAMP2的剪接缺陷或蛋白质截短。由于其罕见性，导致丹农病的基因突变的全貌尚未阐明。
我们分析了3例临床和病理表现与丹农病一致的男性病例。全面的突变分析未能检测到选定的LAMP2外显子的产物，怀疑存在基因组DNA缺失。病例1的基因组连接片段聚合酶链反应分析确定了一个新的由Alu介导的34kb微缺失，该缺失涵盖LAMP2的整个5'-非翻译区和外显子1。在病例2和病例3中，连接聚合酶链反应和Southern印迹分析将断点定位到内含子3中存在的MIRb和（TA）（n）简单重复序列，分别确定了64kb和58kb的缺失，从而缺失了外显子4至10。蛋白质印迹分析证实病例2的索引病例淋巴细胞蛋白提取物中不存在LAMP2。
本文首次报道了由Xq24微缺失导致的丹农病，该微缺失在功能上消除了LAMP2。微缺失机制似乎涉及1次Alu介导的不等位重组和2个涉及富含TA重复序列的染色体断裂点。
