Kehrer-Sawatzki H, Kluwe L, Sandig C, Kohn M, Wimmer K, Krammer U, Peyrl A, Jenne D E, Hansmann I, Mautner V-F
Department of Human Genetics, University of Ulm, Ulm, Germany.
Am J Hum Genet. 2004 Sep;75(3):410-23. doi: 10.1086/423624. Epub 2004 Jul 15.
Detailed analyses of 20 patients with sporadic neurofibromatosis type 1 (NF1) microdeletions revealed an unexpected high frequency of somatic mosaicism (8/20 [40%]). This proportion of mosaic deletions is much higher than previously anticipated. Of these deletions, 16 were identified by a screen of unselected patients with NF1. None of the eight patients with mosaic deletions exhibited the mental retardation and facial dysmorphism usually associated with NF1 microdeletions. Our study demonstrates the importance of a general screening for NF1 deletions, regardless of a special phenotype, because of a high estimated number of otherwise undetected mosaic NF1 microdeletions. In patients with mosaicism, the proportion of cells with the deletion was 91%-100% in peripheral leukocytes but was much lower (51%-80%) in buccal smears or peripheral skin fibroblasts. Therefore, the analysis of other tissues than blood is recommended, to exclude mosaicism with normal cells in patients with NF1 microdeletions. Furthermore, our study reveals breakpoint heterogeneity. The classic 1.4-Mb deletion was found in 13 patients. These type I deletions encompass 14 genes and have breakpoints in the NF1 low-copy repeats. However, we identified a second major type of NF1 microdeletion, which spans 1.2 Mb and affects 13 genes. This type II deletion was found in 8 (38%) of 21 patients and is mediated by recombination between the JJAZ1 gene and its pseudogene. The JJAZ1 gene, which is completely deleted in patients with type I NF1 microdeletions and is disrupted in deletions of type II, is highly expressed in brain structures associated with learning and memory. Thus, its haploinsufficiency might contribute to mental impairment in patients with constitutional NF1 microdeletions. Conspicuously, seven of the eight mosaic deletions are of type II, whereas only one was a classic type I deletion. Therefore, the JJAZ1 gene is a preferred target of strand exchange during mitotic nonallelic homologous recombination. Although type I NF1 microdeletions occur by interchromosomal recombination during meiosis, our findings imply that type II deletions are mediated by intrachromosomal recombination during mitosis. Thus, NF1 microdeletions acquired during mitotic cell divisions differ from those occurring in meiosis and are caused by different mechanisms.
对20例散发型1型神经纤维瘤病（NF1）微缺失患者的详细分析显示，体细胞镶嵌现象的发生率出乎意料地高（20例中有8例[40%]）。这种镶嵌缺失的比例远高于先前的预期。在这些缺失中，有16例是通过对未经过筛选的NF1患者进行筛查发现的。8例存在镶嵌缺失的患者均未表现出通常与NF1微缺失相关的智力发育迟缓及面部畸形。我们的研究表明，无论有无特殊表型，对NF1缺失进行全面筛查都很重要，因为据估计有大量未被检测到的镶嵌型NF1微缺失。对于存在镶嵌现象的患者，外周血白细胞中携带缺失的细胞比例为91% - 100%，但在口腔涂片或外周皮肤成纤维细胞中则低得多（51% - 80%）。因此，建议对血液以外的其他组织进行分析，以排除NF1微缺失患者中正常细胞的镶嵌现象。此外，我们的研究揭示了断点的异质性。13例患者中发现了经典的1.4 Mb缺失。这些I型缺失包含14个基因，断点位于NF1低拷贝重复序列中。然而，我们还鉴定出了第二种主要的NF1微缺失类型，其跨度为1.2 Mb，影响13个基因。在21例患者中有8例（38%）发现了这种II型缺失，它是由JJAZ1基因与其假基因之间的重组介导的。在I型NF1微缺失患者中完全缺失且在II型缺失中被破坏的JJAZ1基因，在与学习和记忆相关的脑结构中高度表达。因此，其单倍剂量不足可能导致遗传性NF1微缺失患者出现智力障碍。值得注意的是，8例镶嵌缺失中有7例为II型，而只有1例是经典的I型缺失。因此，JJAZ1基因是有丝分裂非等位基因同源重组过程中链交换的首选靶点。虽然I型NF1微缺失是在减数分裂期间通过染色体间重组发生的，但我们的研究结果表明，II型缺失是在有丝分裂期间通过染色体内重组介导的。因此，有丝分裂细胞分裂过程中获得的NF1微缺失与减数分裂过程中发生的不同，且由不同机制引起。
