生物谷報道：美國科學(xué)家近日研究發(fā)現(xiàn)，神經(jīng)干細(xì)胞發(fā)育障礙與孤獨癥有關(guān),。研究證實,，神經(jīng)干細(xì)胞缺乏肌細(xì)胞增強(qiáng)子2C（MEF2C）的小鼠具有較小的大腦、更少的神經(jīng)細(xì)胞,，并表現(xiàn)出與雷特氏綜合癥（Rett Syndrome,，孤獨癥的一種）患者相類似的行為。相關(guān)論文6月30日發(fā)表在美國《國家科學(xué)院院刊》（PNAS）上,。
領(lǐng)導(dǎo)此次研究的是美國伯恩漢醫(yī)學(xué)研究所的Stuart A. Lipton,。研究人員發(fā)現(xiàn)，MEF2C會開啟特殊的基因,，這些基因驅(qū)動干細(xì)胞分化成神經(jīng)細(xì)胞,。當(dāng)從小鼠的神經(jīng)干細(xì)胞中刪除MEF2C后，會出現(xiàn)神經(jīng)細(xì)胞的錯誤“分配”,，并伴有嚴(yán)重的發(fā)育問題,。腦部缺乏MEF2C的成年小鼠會表現(xiàn)出反常的焦慮行為，認(rèn)知能力下降,，爪緊抓,，這與患有雷特氏綜合癥的人搓手的顯著特征相類似。
此次研究首次提出,，神經(jīng)干細(xì)胞發(fā)育障礙與并發(fā)的孤獨癥之間存在直接聯(lián)系,。Lipton說：“此次結(jié)果為我們提供了很好的線索來研究雷特氏綜合癥和潛在的其它人類孤獨癥。識別出導(dǎo)致這種缺陷的變異后,，我們能夠追蹤所發(fā)生的情況,。也許我們能夠在小鼠身上進(jìn)行糾正，假如成功的話,，最終也可能在人類身上實現(xiàn),。”（生物谷bioon.com）
生物谷推薦原始出處：
Proc. Natl. Acad. Sci. USA, 10.1073/pnas.0801294105
Syntrophin mutation associated with long QT syndrome through activation of the nNOS–SCN5A macromolecular complex
Kazuo Ueda*,, Carmen Valdivia*, Argelia Medeiros-Domingo, David J. Tester, Matteo Vatta, Gianrico Farrugia¶, Michael J. Ackerman,||, and Jonathan C. Makielski*,||
*Department of Medicine, University of Wisconsin, Madison, WI 53792; Departments of Medicine, Pediatrics, and Molecular Pharmacology and Experimental Therapeutics and ¶Department of Medicine and the Enteric NeuroScience Program, Mayo Clinic, Rochester, MN 55905; and Section of Pediatric Cardiology, Texas Children's Hospital/Baylor College of Medicine, Houston, TX 77030
Edited by David E. Clapham, Harvard Medical School, Boston, MA, and approved April 16, 2008 (received for review February 8, 2008)
Abstract
Mutations in 11 genes that encode ion channels or their associated proteins cause inherited long QT syndrome (LQTS) and account for 75–80% of cases (LQT1–11). Direct sequencing of SNTA1, the gene encoding 1-syntrophin, was performed in a cohort of LQTS patients that were negative for mutations in the 11 known LQTS-susceptibility genes. A missense mutation (A390V-SNTA1) was found in a patient with recurrent syncope and markedly prolonged QT interval (QTc, 530 ms). SNTA1 links neuronal nitric oxide synthase (nNOS) to the nNOS inhibitor plasma membrane Ca-ATPase subtype 4b (PMCA4b); SNTA1 also is known to associate with the cardiac sodium channel SCN5A. By using a GST-fusion protein of the C terminus of SCN5A, we showed that WT-SNTA1 interacted with SCN5A, nNOS, and PMCA4b. In contrast, A390V-SNTA1 selectively disrupted association of PMCA4b with this complex and increased direct nitrosylation of SCN5A. A390V-SNTA1 expressed with SCN5A, nNOS, and PMCA4b in heterologous cells increased peak and late sodium current compared with WT-SNTA1, and the increase was partially inhibited by NOS blockers. Expression of A390V-SNTA1 in cardiac myocytes also increased late sodium current. We conclude that the A390V mutation disrupted binding with PMCA4b, released inhibition of nNOS, caused S-nitrosylation of SCN5A, and was associated with increased late sodium current, which is the characteristic biophysical dysfunction for sodium-channel-mediated LQTS (LQT3). These results establish an SNTA1-based nNOS complex attached to SCN5A as a key regulator of sodium current and suggest that SNTA1 be considered a rare LQTS-susceptibility gene.
