Loss of coordinated expression between ribosomal and mitochondrial genes revealed by comprehensive characterization of a large family with a rare Mendelian disorder.
Loss of coordinated expression between ribosomal and mitochondrial genes revealed by comprehensive characterization of a large family with a rare Mendelian disorder.
复制标题
DOI：
10.1016/j.ygeno.2021.04.020
复制
发表时间：
2021-07
期刊：
影响因子：
4.4
通讯作者：
Cenik ES
中科院分区：
文献类型：
--
作者：
Panici B;Nakajima H;Carlston CM;Ozadam H;Cenik C;Cenik ES
非典型内含子变体是与孟德尔疾病相关的特征不明显但高度普遍的一类改变。在这里，我们报告的第一个RNA表达和剪接分析，从一个家庭的成员携带一个非典型的剪接变异体的内含子RPL 11（c.396+3A>G）。这种突变是导致该家族中的Diamond Blackfan贫血（DBA）的原因，尽管不完全的表达和可变的表达。我们的分析揭示了一个复杂的模式，中断与许多新的路口RPL 11。这些包括RPL 11转录物，其在主要同种型的3'非翻译区（3'UTR）中用晚期终止密码子翻译。我们观察到RPL11转录丰度在携带者之间是相当的，无论症状的严重程度如何。有趣的是，核糖体小亚基和大亚基转录物在除了先天性异常之外还有贫血史的个体中显著过表达。最后，我们发现线粒体组分和RPL 11之间的协调表达在所有载体中丢失，这可能导致可变的表达率。总体而言，这项研究突出了孟德尔疾病的分子表征的家庭中的RNA剪接和表达分析的重要性。
Non-canonical intronic variants are a poorly characterized yet highly prevalent class of alterations associated with Mendelian disorders. Here, we report the first RNA expression and splicing analysis from a family whose members carry a non-canonical splice variant in an intron of RPL11 (c.396+3A>G). This mutation is causative for Diamond Blackfan Anemia (DBA) in this family despite incomplete penetrance and variable expressivity. Our analyses revealed a complex pattern of disruptions with many novel junctions of RPL11. These include an RPL11 transcript that is translated with a late stop codon in the 3’ untranslated region (3’UTR) of the main isoform. We observed that RPL11 transcript abundance is comparable among carriers regardless of symptom severity. Interestingly, both the small and large ribosomal subunit transcripts were significantly overexpressed in individuals with a history of anemia in addition to congenital abnormalities. Finally, we discovered that coordinated expression between mitochondrial components and RPL11 was lost in all carriers, which may lead to variable expressivity. Overall, this study highlights the importance of RNA splicing and expression analyses in families for molecular characterization of Mendelian diseases.
登录
查看更多内容
影响因子：
3.5
作者：
Chardon, Jodi Warman;Smith, A. C.;Dyment, D. A.
通讯作者：
Dyment, D. A.
影响因子：
14.9
作者：
Frankish A;Diekhans M;Ferreira AM;Johnson R;Jungreis I;Loveland J;Mudge JM;Sisu C;Wright J;Armstrong J;Barnes I;Berry A;Bignell A;Carbonell Sala S;Chrast J;Cunningham F;Di Domenico T;Donaldson S;Fiddes IT;García Girón C;Gonzalez JM;Grego T;Hardy M;Hourlier T;Hunt T;Izuogu OG;Lagarde J;Martin FJ;Martínez L;Mohanan S;Muir P;Navarro FCP;Parker A;Pei B;Pozo F;Ruffier M;Schmitt BM;Stapleton E;Suner MM;Sycheva I;Uszczynska-Ratajczak B;Xu J;Yates A;Zerbino D;Zhang Y;Aken B;Choudhary JS;Gerstein M;Guigó R;Hubbard TJP;Kellis M;Paten B;Reymond A;Tress ML;Flicek P
通讯作者：
Flicek P
DOI：
10.1155/2012/529179
发表时间：
2012
期刊：
Journal of signal transduction
影响因子：
--
作者：
Akakura S;Gelman IH
通讯作者：
Gelman IH
影响因子：
--
作者：
Fancello L;Kampen KR;Hofman IJ;Verbeeck J;De Keersmaecker K
通讯作者：
De Keersmaecker K
影响因子：
17.1
作者：
Cummings BB;Marshall JL;Tukiainen T;Lek M;Donkervoort S;Foley AR;Bolduc V;Waddell LB;Sandaradura SA;O'Grady GL;Estrella E;Reddy HM;Zhao F;Weisburd B;Karczewski KJ;O'Donnell-Luria AH;Birnbaum D;Sarkozy A;Hu Y;Gonorazky H;Claeys K;Joshi H;Bournazos A;Oates EC;Ghaoui R;Davis MR;Laing NG;Topf A;Genotype-Tissue Expression Consortium;Kang PB;Beggs AH;North KN;Straub V;Dowling JJ;Muntoni F;Clarke NF;Cooper ST;Bönnemann CG;MacArthur DG
通讯作者：
MacArthur DG