Paternal mosaicism of an STXBP1 mutation in OS
Paternal mosaicism of an STXBP1 mutation in OS
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DOI：
10.1111/j.1399-0004.2010.01575.x
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发表时间：
2011-11-01
影响因子：
3.5
通讯作者：
Matsumoto, N.
中科院分区：
文献类型：
--
作者：
Saitsu, H.;Hoshino, H.;Matsumoto, N.
大田原综合征 (OS) 是最严重和最早的癫痫形式之一。我们最近发现 STXBP1 的从头突变是 OS 的重要原因。在这里，我们报告了 STXBP1 突变的父系体细胞嵌合现象。患儿1月龄时出现痉挛，发作间期脑电图呈抑制-爆发型，诊断为OS。她的 STXBP1 存在杂合 c.902+5G>A 突变，该突变影响外显子 10 的供体剪接，导致转录本中内含子 10 序列插入 138 bp。突变转录物有一个过早的终止密码子，并被来自患者的淋巴母细胞中无义介导的 mRNA 降解所降解。对临床上未受影响的亲本 DNA 进行高分辨率熔解分析表明，父亲是该突变的体细胞嵌合体，测序也表明了这一点。用从血液、唾液、口腔细胞和指甲中提取的父本 DNA 样本扩增的 PCR 产物克隆表明，分别有 5.3%、8.7%、11.9% 和 16.9% 的等位基因携带突变。这是 STXBP1 突变体细胞嵌合体的首次报告，这对 OS 的遗传咨询具有重要意义。
Ohtahara syndrome (OS) is one of the most severe and earliest forms of epilepsy. We have recently identified that the de novo mutations of STXBP1 are important causes for OS. Here we report a paternal somatic mosaicism of an STXBP1 mutation. The affected daughter had onset of spasms at 1 month of age, and interictal electroencephalogram showed suppression-burst pattern, leading to the diagnosis of OS. She had a heterozygous c.902+5G>A mutation of STXBP1, which affects donor splicing of exon 10, resulting in 138-bp insertion of intron 10 sequences in the transcript. The mutant transcript had a premature stop codon, and was degraded by nonsense-mediated mRNA decay in lymphoblastoid cells derived from the patient. High-resolution melting analysis of clinically unaffected parental DNAs suggested that the father was somatic mosaic for the mutation, which was also suggested by sequencing. Cloning of PCR products amplified with the paternal DNA samples extracted from blood, saliva, buccal cells, and nails suggested that 5.3%, 8.7%, 11.9%, and 16.9% of alleles harbored the mutation, respectively. This is a first report of somatic mosaicism of an STXBP1 mutation, which has implications in genetic counseling of OS.