DNA-based prenatal diagnosis of harlequin ichthyosis and characterization of ABCA12 mutation consequences
DNA-based prenatal diagnosis of harlequin ichthyosis and characterization of ABCA12 mutation consequences
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DOI：
10.1038/sj.jid.5700617
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发表时间：
2007-03-01
影响因子：
6.5
通讯作者：
Shimizu, Hiroshi
中科院分区：
文献类型：
--
作者：
Akiyama, Masashi;Titeux, Matthias;Shimizu, Hiroshi
在确定 ABCA12 为致病基因之前，丑角鱼鳞病 (HI) 的产前诊断 (PD) 都是通过胎儿皮肤活检样本的电子显微镜观察进行的。我们报告了第一例基于 HI DNA 的 PD 病例。 ABCA12 的直接序列分析显示，已故先证者是两个新突变的复合杂合子。母体无义突变p。 Ser1249Term 可能会导致无义介导的信使 RNA 衰变。父本突变 C. 7436G > A 影响外显子 50 的最后一个密码子，预计是剪接位点突变。第三次怀孕时，父母要求进行腹膜透析。对妊娠 17 周时羊水细胞的胎儿基因组 DNA 进行直接序列分析显示，胎儿是两种突变的复合杂合子。父母要求终止妊娠。对流产培养角质形成细胞的 ABCA12 转录物的分析表明，存在来自携带剪接位点突变的等位基因的六种异常剪接产物。其中四个导致过早终止密码子，而另外两个产生缩短的蛋白质，缺少第二个 ATP 结合盒中的 21 和 31 个氨基酸。该报告提供了 HI 中残留 ABCA12 表达的证据，并证明了早期基于 DNA 的 HI PD 的有效性。
Until the identification of ABCA12 as the causative gene, prenatal diagnosis (PD) for harlequin ichthyosis (HI) had been performed by electron microscopic observation of fetal skin biopsy samples. We report the first case of HI DNA-based PD. Direct sequence analysis of ABCA12 revealed that the deceased proband was a compound heterozygote for two novel mutations. The maternal nonsense mutation p. Ser1249Term likely leads to nonsense-mediated messenger RNA decay. The paternal mutation c. 7436G > A affects the last codon of exon 50 and was expected to be a splice site mutation. For their third pregnancy, the parents requested PD. Direct sequence analysis of fetal genomic DNA from amniotic fluid cells at 17 weeks gestation revealed the fetus was a compound heterozygote for both mutations. The parents requested the pregnancy to be terminated. Analysis of ABCA12 transcripts of cultured keratinocytes from the abortus showed the presence of six abnormally spliced products from the allele carrying the splice site mutation. Four of them lead to premature termination codons whereas the two others produced shortened proteins missing 21 and 31 amino acids from the second ATP-binding cassette. This report provides evidence for residual ABCA12 expression in HI, and demonstrates the efficiency of early DNA-based PD of HI.