Multiple correcting COL17A1 mutations in patients with revertant mosaicism of epidermolysis bullosa
Multiple correcting COL17A1 mutations in patients with revertant mosaicism of epidermolysis bullosa
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DOI：
10.1086/497344
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发表时间：
2005-11-01
影响因子：
9.8
通讯作者：
Jonkman, MF
中科院分区：
文献类型：
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作者：
Pasmooij, AMG;Pas, HH;Jonkman, MF
通过遗传突变的体细胞回复的回复嵌合现象已被描述用于许多遗传疾病。有几种机制可能是这种逆转过程的基础，如基因转换、交换、真回复突变和第二位点突变。在这里，我们报告了两个不相关的先证者与非Herlitz交界表皮大疱性，一种常染色体隐性遗传性皮肤病，由于在COL 17 A1基因突变的回复嵌合体的发生多个校正。对皮肤活检标本进行免疫荧光显微镜和激光解剖显微镜检查，然后进行DNA和RNA分析。在患者1中，在来自手臂的样本中鉴定出真正的回复突变3781 T-> C，并且在来自中指的样本中鉴定出第二位点突变4463-1G -> A，其补偿了由遗传的4424-5insC突变引起的移码。患者2显示，除了手臂和手部位标本中的两个不同的基因转换事件，这两个事件都纠正了1706 delA突变之外，脚踝标本中的第二个位点突变（3782 G-> C），它阻止了3781 C-> T无义突变（R1226 X）导致的蛋白质过早结束。因此，两种遗传突变，父亲以及母亲，在所述患者的不同细胞簇中通过不同的回复事件回复至少一次。在同一个病人体内发生多个纠正突变表明，体内回复并不像人们通常认为的那样罕见。此外，在男性患者中，XVII型胶原阳性角质形成细胞的镶嵌图案存在于临床未受影响和受影响的皮肤中。后一种观察结果可能会使逆转被忽视，并且可能比预期更频繁地发生。
Revertant mosaicism by somatic reversion of inherited mutations has been described for a number of genetic diseases. Several mechanisms can underlie this reversion process, such as gene conversion, crossing-over, true back mutation, and second-site mutation. Here, we report the occurrence of multiple corrections in two unrelated probands with revertant mosaicism of non-Herlitz junctional epidermolysis bullosa, an autosomal recessive genodermatosis due to mutations in the COL17A1 gene. Immunofluorescence microscopy and laser dissection microscopy, followed by DNA and RNA analysis, were performed on skin biopsy specimens. In patient 1, a true back mutation, 3781T -> C, was identified in the specimen from the arm, and a second-site mutation, 4463-1G -> A, which compensated for the frameshift caused by the inherited 4424-5insC mutation, was identified in the 3' splice site of exon 55 in a specimen from the middle finger. Patient 2 showed-besides two distinct gene conversion events in specimens from the arm and hand sites, both of which corrected the 1706delA mutation-a second-site mutation (3782G -> C) in an ankle specimen, which prevented the premature ending of the protein by the 3781C -> T nonsense mutation (R1226X). Thus, both inherited mutations, paternal as well as maternal, reverted at least once by different reversion events in distinct cell clusters in the described patients. The occurrence of multiple correcting mutations within the same patient indicates that in vivo reversion is less unusual than was generally thought. Furthermore, in the male patient, mosaic patterns of type XVII collagen-positive keratinocytes were present in clinically unaffected and affected skin. This latter observation makes it likely that reversion may be overlooked and may happen more often than expected.