Chromosomal inversions as a hidden disease-modifying factor for somatic recombination phenotypes.
Chromosomal inversions as a hidden disease-modifying factor for somatic recombination phenotypes.
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DOI：
10.1172/jci.insight.97595
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发表时间：
2018-03
期刊：
影响因子：
8
通讯作者：
T. Nomura;Shotaro Suzuki;T. Miyauchi;M. Takeda;S. Shinkuma;Y. Fujita;W. Nishie;M. Akiyama;H. Shimizu
中科院分区：
文献类型：
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作者：
T. Nomura;Shotaro Suzuki;T. Miyauchi;M. Takeda;S. Shinkuma;Y. Fujita;W. Nishie;M. Akiyama;H. Shimizu
杂合染色体倒位抑制重组。因此，它们可能潜在地影响人类疾病的重组相关表型，但没有研究证实这一假设。在这里，我们描述了一个35岁的男子与严重的先天性鱼鳞病。突变分析显示KRT 10在17q21.2上存在杂合剪接位点突变，c.1374-2A>G（p.Ser458Argfs*120）。这种突变以前曾在I型鱼鳞病（IWC-I）患者中报道过，IWC-I是一种突出的皮肤病，其特征是频繁发生重组诱导的致病突变逆转。有趣的是，与典型的IWC-I病例相比，该患者的回复突变皮肤区域数量大大减少。G显带核型分析显示，该患者携带杂合的非致病性倒位inv（17）（p13 q12），其长臂断裂点随后通过FISH精确到染色体位置（chr 17：36，544，407 - 36，639，830）。总的来说，通过体细胞重组的回复突变嵌合体的唯一机会似乎涉及KRT 10突变和倒位断裂点之间的重组。实际上，在所检查的回复突变体点中，KRT 10突变通过从17 q12上的染色体位置（chr 17：36，915，505 - 37，060，285）开始的体细胞重组而减少。这项研究提供了第一个证据，以我们的知识暗示染色体倒位作为一个潜在的修改器的临床表型。此外，在重组抑制患者中回复突变点的发生率降低表明体细胞重组是IWC-1中回复突变嵌合的主要机制。
Heterozygous chromosomal inversions suppress recombination. Therefore, they may potentially influence recombination-associated phenotypes of human diseases, but no studies have verified this hypothesis. Here, we describe a 35-year-old man with severe congenital ichthyosis. Mutation analysis revealed a heterozygous splice-site mutation, c.1374-2A>G (p.Ser458Argfs*120), in KRT10 on 17q21.2. This mutation was previously reported in patients with ichthyosis with confetti type I (IWC-I), a prominent skin disease characterized by the frequent occurrence of recombination-induced reversion of pathogenic mutations. Intriguingly, the number of revertant skin areas in this patient is considerably reduced compared with typical IWC-I cases. G-banded karyotyping revealed that the patient harbors a heterozygous nonpathogenic inversion, inv(17)(p13q12), whose long-arm breakpoint was subsequently refined to chromosomal positions (chr17: 36,544,407-36,639,830) via FISH. Collectively, the only chance of revertant mosaicism through somatic recombination appears to involve recombination between the KRT10 mutation and the inversion breakpoint. Indeed, in the examined revertant spot, the KRT10 mutation was diminished by somatic recombination starting from chromosomal positions (chr17: 36,915,505-37,060,285) on 17q12. This study provides the first evidence to our knowledge implicating chromosomal inversions as a potential modifier of clinical phenotypes. Furthermore, the reduced occurrence of revertant spots in the recombination-suppressed patient suggests that somatic recombination is the main mechanism of revertant mosaicism in IWC-I.