2012年9月2日 訊 /生物谷BIOON/ --新生兒中大約有2%-3%的兒童從一出生就患上了智力障礙,，這或許是由一種遺傳缺失所致，但是在80%的發(fā)病例子中或許是由于某些基因“搗鬼”,，近日,，來自魯汶大學(xué)的研究者揭示了蛋白質(zhì)HUWE1產(chǎn)量的增加或許是某些智力障礙發(fā)病的原因。相關(guān)研究成果刊登在了國際雜志The American Journal of Human Genetics上,。
HUWE1可以在大腦中調(diào)節(jié)許多蛋白質(zhì)的表達(dá),，其對于新型治療方法具有重要的意義，深入研究其功能對于理解智力障礙非常重要,。智力障礙常常歸咎于外部影響因子,，如在出生時供養(yǎng)不足或者遺傳物質(zhì)缺失等。有將近15%的病人的致病原因是由于其X染色體的部分缺失,，這就是所謂的X連鎖智力障礙（XLID）,，盡管研究者在不斷研究，但是引發(fā)XLID的效應(yīng)基因至今仍沒有被鑒別出來,。
研究者Guy和其同事通過研究發(fā)現(xiàn)了引發(fā)XLID的新基因,，在幾年前，其發(fā)現(xiàn)X染色體片段的復(fù)制可以導(dǎo)致高濃度HSD17B10蛋白和HUWE1蛋白的產(chǎn)生,，Guy教授說,，這兩種蛋白質(zhì)在對于大腦記憶中樞非常關(guān)鍵，但是我們并不清楚到底是哪一種基因?qū)е铝薠LID的病癥,。通過與歐洲,、澳大利亞等處的研究人員共同研究，我們發(fā)現(xiàn)HUWE1是關(guān)鍵的因子,，其濃度的增加可以導(dǎo)致智力障礙的發(fā)生,。
研究者的研究為治療XLID提供了新的思路,，這也幫助我們檢測HUWE1的復(fù)制以及錯誤發(fā)生，這項研究中,，研究者的研究為我們更好地理解HUWE1蛋白提供了幫助,，尤其是在大腦功能的角色扮演上更是提供了極大的幫助。（生物谷Bioon.com）
編譯自：Too Much Protein HUWE1 Causes Intellectual Disability
doi:10.1016/j.ajhg.2012.06.010
PMC:
PMID:
Copy-Number Gains of HUWE1 Due to Replication- and Recombination-Based Rearrangements
Guy Froyen1, 2, , , Stefanie Belet1, 2, Francisco Martinez3, Cíntia Barros Santos-Rebouças4, Matthias Declercq1, 2, Jelle Verbeeck1, 2, Lene Donckers1, 2, Siren Berland5, 6, Sonia Mayo3, Monica Rosello3, Márcia Mattos Gonçalves Pimentel4, Natalia Fintelman-Rodrigues4, Randi Hovland6, Suely Rodrigues dos Santos7, F. Lucy Raymond8, Tulika Bose9, Mark A. Corbett9, Leslie Sheffield9, Conny M.A. van Ravenswaaij-Arts10, Trijnie Dijkhuizen10, Charles Coutton11, 12, 13, Veronique Satre11, 12, 13, Victoria Siu14 and Peter Marynen2
We previously reported on nonrecurrent overlapping duplications at Xp11.22 in individuals with nonsyndromic intellectual disability (ID) harboring HSD17B10, HUWE1, and the microRNAs miR-98 and let-7f-2 in the smallest region of overlap. Here, we describe six additional individuals with nonsyndromic ID and overlapping microduplications that segregate in the families. High-resolution mapping of the 12 copy-number gains reduced the minimal duplicated region to the HUWE1 locus only. Consequently, increased mRNA levels were detected for HUWE1, but not HSD17B10. Marker and SNP analysis, together with identification of two de novo events, suggested a paternally derived intrachromosomal duplication event. In four independent families, we report on a polymorphic 70 kb recurrent copy-number gain, which harbors part of HUWE1 (exon 28 to 3 untranslated region), including miR-98 and let-7f-2. Our findings thus demonstrate that HUWE1 is the only remaining dosage-sensitive gene associated with the ID phenotype. Junction and in silico analysis of breakpoint regions demonstrated simple microhomology-mediated rearrangements suggestive of replication-based duplication events. Intriguingly, in a single family, the duplication was generated through nonallelic homologous recombination (NAHR) with the use of HUWE1-flanking imperfect low-copy repeats, which drive this infrequent NAHR event. The recurrent partial HUWE1 copy-number gain was also generated through NAHR, but here, the homologous sequences used were identified as TcMAR-Tigger DNA elements, a template that has not yet been reported for NAHR. In summary, we showed that an increased dosage of HUWE1 causes nonsyndromic ID and demonstrated that the Xp11.22 region is prone to recombination- and replication-based rearrangements. /P>
