Functional characterization and targeted correction of ATM mutations identified in Japanese patients with ataxia-telangiectasia.
Functional characterization and targeted correction of ATM mutations identified in Japanese patients with ataxia-telangiectasia.
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DOI：
10.1002/humu.21632
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发表时间：
2012-01
期刊：
影响因子：
3.9
通讯作者：
Gatti, Richard A.
中科院分区：
文献类型：
--
作者：
Nakamura, Kotoka;Du, Liutao;Tunuguntla, Rashmi;Fike, Francesca;Cavalieri, Simona;Morio, Tomohiro;Mizutani, Shuki;Brusco, Alfredo;Gatti, Richard A.
关键词：
研究进行性神经系统疾病共济失调毛细血管扩张症（A-T）的研究人员最近面临的挑战是识别突变，其影响可能通过突变靶向疗法减轻。我们研究了 8 个日本 A-T 患者 (JPAT) 家族的 ATM 突变，并能够识别出所有 16 种突变。先证者是七个家族的复合杂合子，其中一个（JPAT2）是移码突变纯合子。除了 JPAT6 家族中发现的 c.748C>T 和 JPAT11/12 家族中发现的 c.2639−384A>G 之外，所有突变（四个移码、两个无义突变、四个大型基因组缺失和六个影响剪接）都是新突变。使用已建立的患者 JPAT11 的淋巴母细胞系 (LCL)，通过暴露于旨在纠正假外显子剪接突变的反义吗啉寡核苷酸，ATM 蛋白恢复至接近野生型的水平。此外，在来自患者 JPAT8/9（无义突变杂合携带者）的 LCL 中，ATM 水平也可以通过暴露于通读化合物 (RTC) 来部分恢复：氨基糖苷类 G418 和我们实验室鉴定的新型小分子 RTC13。总而言之，我们的结果表明，对影响 ATM 基因的各种突变进行筛选和功能表征可以更好地识别最有可能从快速发展的突变靶向治疗技术中受益的 A-T 患者。
A recent challenge for investigators studying the progressive neurological disease ataxia-telangiectasia (A-T) is to identify mutations whose effects might be alleviated by mutation-targeted therapies. We studied ATM mutations in eight families of Japanese A-T patients (JPAT) and were able to identify all 16 mutations. The probands were compound heterozygotes in seven families, and one (JPAT2) was homozygous for a frameshift mutation. All mutations - four frameshift, two nonsense, four large genomic deletions, and six affecting splicing - were novel except for c.748C>T found in family JPAT6 and c.2639−384A>G found in family JPAT11/12. Using an established lymphoblastoid cell line (LCL) of patient JPAT11, ATM protein was restored to levels approaching wildtype by exposure to an antisense morpholino oligonucleotide designed to correct a pseudoexon splicing mutation. In addition, in an LCL from patient JPAT8/9, a heterozygous carrier of a nonsense mutation, ATM levels could also be partially restored by exposure to readthrough compounds (RTC): an aminoglycoside, G418, and a novel small molecule identified in our laboratory, RTC13. Taken together, our results suggest that screening and functional characterization of the various sorts of mutations affecting the ATM gene can lead to better identification of A-T patients who are most likely to benefit from rapidly developing mutation-targeted therapeutic technologies.
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影响因子：
14.9
作者：
Cartegni, L;Wang, JH;Krainer, AR
通讯作者：
Krainer, AR
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1.9
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Brusco, Alfredo
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YODER, F
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