两例携带UBE3A新突变的Angelman综合征患者的临床表型及遗传学分析  

Clinical and genetic analysis of two unrelated patients with Angelman syndrome and novel UBE3A mutations

作　　者：徐慧慧[1] 季星[1] 徐燕[1] 刘晓青[1] 张静敏[1] 陈颖伟[1] 肖冰[1] 

机构地区：[1]上海交通大学医学院附属新华医院上海市儿科医学研究所,200092

出　　处：《中华医学遗传学杂志》2017年第6期826-830,共5页Chinese Journal of Medical Genetics

基　　金：上海交通大学医学院科技基金项目（14XJL0073）;上海市卫生局青年项目基金（20144Y0086）;上海市卫计委面上项目（201540054）;国家自然科学基金青年科学基金（81501249）

摘　　要：目的明确两例Angelman综合征（Angelman syndrome，AS）患者的遗传学病因，并分析其基因型与表型的关系。方法首先应用染色体核型及染色体芯片技术分析患者是否携带染色体15q11．2区域大片段缺失或重复以及单亲二倍体。然后对AS关键致病基因UBE3A编码区及邻近内含子区域进行突变分析，并通过逆转录PCR检测剪切突变对基因转录的影响。结果测序结果显示家系1先证者及母亲携带一个UBE3A基因杂合剪切突变IVS15—1G〉C；逆转录-PCR结果显示家系1先证者及母亲UBE3A基因转录后杂合缺失54／59个核苷酸，导致缺失18个氨基酸或提前终止翻译，破坏UBE3A蛋白关键HECT结构域；核型分析及染色体芯片结果均正常；先证者表现为严重智力低下、共济失调、癫痫及不自觉发笑等典型AS症状。家系2先证者、先证者弟弟及母亲携带UBE3A基因C．2540C〉T杂合错义突变（P．P847L）；核型分析及染色体芯片结果均正常；先证者及弟弟表现为智力低下、轻微共济失调及不自觉发笑等。结论UBE3A基因第16外显子IVS15—1G〉C和C．2540C〉T突变分别为两家系的致病原因，均为未报道过的新突变。UBE3A基因大片段缺失对患者临床表型影响更明显。Objective To explore the genetic cause for two familial Angelman syndrome cases and correlation between the clinical phenotypes and their genetic basis. Methods Karyotyping analysis and microarray assay were carried out to exclude chromosome anomalies and uniparental disomy. The UBESA gene was analyzed for potential point mutations, deletions, insertions and splice site mutations. Reverse transcription PCR was used to evaluate splicing mutation of the RNA transcripts. Results DNA sequencing showed the proband of family 1 has carried a novel maternal UBE3A splice acceptor site mutation, resulting in a guanine to-cytosine transversion （IVS15-1G〉〉C）. Reverse transcription PCR revealed the proband and his mother both carried heterozygous mutant transcripts with loss of 54 and 59 nucleotides in exon 16, respectively. The proband displayed severe mental retardation, ataxia, seizures and inappropriate laughter. The siblings of family 2 has carried a novel maternal missense mutation in exon 16 of the UBE3A gene （c. 2540 C〉T）. She also presented with mental retardation, absent speech, mild ataxia and inappropriate laughter. Conclusion The novel IVS15-1G〉C and c. 2540 C〉T mutations of the UBEaA gene probably underlie the AS in the two families. Compared with small-scale mutations, larger fragments mutations can produce more severe phenotypes.

关 键 词：ANGELMAN综合征 UBE3A基因 剪切突变 错义突变 智力低下 

分 类 号：R748[医药卫生—神经病学与精神病学]