小柯机器人

德国马克斯普朗克分子遗传学研究所Denes Hnisz等研究人员合作发现罕见遗传病中异常的相分离和核仁功能障碍。该研究于2023年2月8日在线发表于国际一流学术期刊《自然》。

研究人员发现，无序区域的一个疾病相关变异的亚群改变相分离，导致核仁错配并破坏核仁功能。研究人员在HMGB1中发现了新生移码变异，导致了短指骨畸形、多指畸形和胫骨再生障碍性综合征，这是一种罕见的复杂畸形综合征。移码将HMGB1本质无序的酸性尾部替换为富含精氨酸的碱性尾部。突变尾改变HMGB1的相分离，增强其向核仁的分配，导致核仁功能障碍。

研究人员建立了一个包含20多万个无序羧基尾变体的目录，并确定了在转录因子和其他蛋白质中产生富含精氨酸的基本尾的600多个移码。对于测试的13个疾病相关变异中的12个，突变增强了核仁的分配，并且几个变异改变了rRNA的生物发生。这些数据确定了一种罕见的复杂综合征的病因，并提示大量的遗传变异可能导致人类核仁和其他生物分子凝聚物失调。

研究人员表示，蛋白质编码基因的遗传变异与疾病有关。然而，大多数变异的功能影响是未知的，因为它们发生在具有不明确功能的内在无序蛋白质区域。本质无序区域可以介导相分离和生物分子凝聚物的形成，如核仁。这表明，紊乱蛋白的突变可能改变凝聚物的性质和功能。

附：英文原文

Title: Aberrant phase separation and nucleolar dysfunction in rare genetic diseases

Author: Mensah, Martin A., Niskanen, Henri, Magalhaes, Alexandre P., Basu, Shaon, Kircher, Martin, Sczakiel, Henrike L., Reiter, Alisa M. V., Elsner, Jonas, Meinecke, Peter, Biskup, Saskia, Chung, Brian H. Y., Dombrowsky, Gregor, Eckmann-Scholz, Christel, Hitz, Marc Phillip, Hoischen, Alexander, Holterhus, Paul-Martin, Hlsemann, Wiebke, Kahrizi, Kimia, Kalscheuer, Vera M., Kan, Anita, Krumbiegel, Mandy, Kurth, Ingo, Leubner, Jonas, Longardt, Ann Carolin, Moritz, Jrg D., Najmabadi, Hossein, Skipalova, Karolina, Snijders Blok, Lot, Tzschach, Andreas, Wiedersberg, Eberhard, Zenker, Martin, Garcia-Cabau, Carla, Buschow, Ren, Salvatella, Xavier, Kraushar, Matthew L., Mundlos, Stefan, Caliebe, Almuth, Spielmann, Malte, Horn, Denise, Hnisz, Denes

Issue&Volume: 2023-02-08

Abstract: Thousands of genetic variants in protein-coding genes have been linked to disease. However, the functional impact of most variants is unknown as they occur within intrinsically disordered protein regions that have poorly defined functions1,2,3. Intrinsically disordered regions can mediate phase separation and the formation of biomolecular condensates, such as the nucleolus4,5. This suggests that mutations in disordered proteins may alter condensate properties and function6,7,8. Here we show that a subset of disease-associated variants in disordered regions alter phase separation, cause mispartitioning into the nucleolus and disrupt nucleolar function. We discover de novo frameshift variants in HMGB1 that cause brachyphalangy, polydactyly and tibial aplasia syndrome, a rare complex malformation syndrome. The frameshifts replace the intrinsically disordered acidic tail of HMGB1 with an arginine-rich basic tail. The mutant tail alters HMGB1 phase separation, enhances its partitioning into the nucleolus and causes nucleolar dysfunction. We built a catalogue of more than 200,000 variants in disordered carboxy-terminal tails and identified more than 600 frameshifts that create arginine-rich basic tails in transcription factors and other proteins. For 12 out of the 13 disease-associated variants tested, the mutation enhanced partitioning into the nucleolus, and several variants altered rRNA biogenesis. These data identify the cause of a rare complex syndrome and suggest that a large number of genetic variants may dysregulate nucleoli and other biomolecular condensates in humans.

DOI: 10.1038/s41586-022-05682-1

Source: https://www.nature.com/articles/s41586-022-05682-1

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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