A novel mutation in the promoter of RARS2 causes pontocerebellar hypoplasia in two siblings.
A novel mutation in the promoter of RARS2 causes pontocerebellar hypoplasia in two siblings.
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DOI：
10.1038/jhg.2015.31
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发表时间：
2015-07
影响因子：
3.5
通讯作者：
del Gaudio D
中科院分区：
文献类型：
--
作者：
Li Z;Schonberg R;Guidugli L;Johnson AK;Arnovitz S;Yang S;Scafidi J;Summar ML;Vezina G;Das S;Chapman K;del Gaudio D
脑桥小脑发育不全（PCH）的特征是小脑发育不全和萎缩，可变脑桥萎缩，小头畸形，严重的精神和运动障碍和癫痫发作。在10种形式的PCH中，有8种报告了11个基因的突变。线粒体乙酰转移RNA合成酶基因（RARS 2）的隐性突变最近与PCH 6型相关，其特征是早发性脑病，伴有氧化磷酸化缺陷的迹象。在这里，我们描述了两名临床诊断为PCH的兄弟姐妹的临床表现、神经影像学检查结果和分子特征，他们表现出一种新型变体（c.- 2A>G）在纯合状态的RARS 2基因的5′-UTR中。这种变异是通过对已知参与PCH的9个基因的下一代测序测试确定的。基因表达和功能研究表明，c. 2A>G序列改变通过降低RARS 2启动子活性直接导致患者中RARS 2信使RNA表达降低，从而提供证据表明RARS 2启动子中的突变可能代表PCH 6的新致病机制。
Pontocerebellar hypoplasia (PCH) is characterized by hypoplasia and atrophy of the cerebellum, variable pontine atrophy, microcephaly, severe mental and motor impairments and seizures. Mutations in 11 genes have been reported in 8 out of 10 forms of PCH. Recessive mutations in the mitochondrial arginyl-transfer RNA synthetase gene (RARS2) have been recently associated with PCH type 6, which is characterized by early-onset encephalopathy with signs of oxidative phosphorylation defect. Here we describe the clinical presentation, neuroimaging findings and molecular characterizations of two siblings with a clinical diagnosis of PCH who displayed a novel variant (c.-2A>G) in the 5′-UTR of the RARS2 gene in the homozygous state. This variant was identified through next-generation sequencing testing of a panel of nine genes known to be involved in PCH. Gene expression and functional studies demonstrated that the c.-2A>G sequence change directly leads to a reduced RARS2 messenger RNA expression in the patients by decreasing RARS2 promoter activity, thus providing evidence that mutations in the RARS2 promoter are likely to represent a new causal mechanism of PCH6.
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影响因子：
2
作者：
Rankin, Julia;Brown, Ruth;Brown, Garry
通讯作者：
Brown, Garry
影响因子：
64.5
作者：
Karaca E;Weitzer S;Pehlivan D;Shiraishi H;Gogakos T;Hanada T;Jhangiani SN;Wiszniewski W;Withers M;Campbell IM;Erdin S;Isikay S;Franco LM;Gonzaga-Jauregui C;Gambin T;Gelowani V;Hunter JV;Yesil G;Koparir E;Yilmaz S;Brown M;Briskin D;Hafner M;Morozov P;Farazi TA;Bernreuther C;Glatzel M;Trattnig S;Friske J;Kronnerwetter C;Bainbridge MN;Gezdirici A;Seven M;Muzny DM;Boerwinkle E;Ozen M;Baylor Hopkins Center for Mendelian Genomics;Clausen T;Tuschl T;Yuksel A;Hess A;Gibbs RA;Martinez J;Penninger JM;Lupski JR
通讯作者：
Lupski JR
影响因子：
30.8
作者：
Mochida, Ganeshwaran H.;Ganesh, Vijay S.;de Michelena, Maria I.;Dias, Hugo;Atabay, Kutay D.;Kathrein, Katie L.;Huang, Hsuan-Ting;Hill, R. Sean;Felie, Jillian M.;Rakiec, Daniel;Gleason, Danielle;Hill, Anthony D.;Malik, Athar N.;Barry, Brenda J.;Partlow, Jennifer N.;Tan, Wen-Hann;Glader, Laurie J.;Barkovich, A. James;Dobyns, William B.;Zon, Leonard I.;Walsh, Christopher A.
通讯作者：
Walsh, Christopher A.
影响因子：
14.9
作者：
Nakagawa S;Niimura Y;Gojobori T;Tanaka H;Miura K
通讯作者：
Miura K
影响因子：
9.8
作者：
Edvardson, Simon;Shaag, Avraham;Elpeleg, Orly
通讯作者：
Elpeleg, Orly