A homozygous PDE6D mutation in Joubert syndrome impairs targeting of farnesylated INPP5E protein to the primary cilium.
A homozygous PDE6D mutation in Joubert syndrome impairs targeting of farnesylated INPP5E protein to the primary cilium.
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DOI：
10.1002/humu.22470
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发表时间：
2014-01
期刊：
影响因子：
3.9
通讯作者：
Attie-Bitach, Tania
中科院分区：
文献类型：
--
作者：
Thomas, Sophie;Wright, Kevin J.;Le Corre, Stephanie;Micalizzi, Alessia;Romani, Marta;Abhyankar, Avinash;Saada, Julien;Perrault, Isabelle;Amiel, Jeanne;Litzler, Julie;Filhol, Emilie;Elkhartoufi, Nadia;Kwong, Mandy;Casanova, Jean-Laurent;Boddaert, Nathalie;Baehr, Wolfgang;Lyonnet, Stanislas;Munnich, Arnold;Burglen, Lydie;Chassaing, Nicolas;Encha-Ravazi, Ferechte;Vekemans, Michel;Gleeson, Joseph G.;Valente, Enza Maria;Jackson, Peter K.;Drummond, Iain A.;Saunier, Sophie;Attie-Bitach, Tania
Joubert综合征（JS）的特点是小脑结构明显缺陷，即“磨牙征”。JS具有遗传异质性，迄今已鉴定的18个基因都是纤毛生物发生和/或功能所必需的。在视神经缺损、肾发育不全和多指畸形相关的JS近亲家族中，结合外显子组测序和作图发现PDE6D纯合剪接位点突变，编码戊酰结合蛋白。我们发现斑马鱼的pde6d缺失导致肾脏和视网膜发育异常，野生型而非突变型pde6d能够挽救这种表型。蛋白质组学分析发现，INPP5E是PDE6D的一种新型丙烯基依赖货物，其突变也会导致JS或MORM综合征。突变的PDE6D显示与INPP5E结合减少，INPP5E不能定位到患者成纤维细胞和组织中的初级纤毛。此外，突变体PDE6D不能与gtp结合的ARL3结合，而ARL3是PDE6D结合的INPP5E的货物释放因子。总之，这些结果表明PDE6D是INPP5E纤毛靶向所必需的，并表明PDE6D在将其他前置化蛋白靶向纤毛方面具有更广泛的作用。本研究确定PDE6D是一种新的JS疾病基因，并提供了纤毛病中戊酰结合依赖性转运的第一个证据。
Joubert syndrome (JS) is characterized by a distinctive cerebellar structural defect, namely the « molar tooth sign ». JS is genetically heterogeneous, involving 18 genes identified to date, which are all required for cilia biogenesis and/or function. In a consanguineous family with JS associated with optic nerve coloboma, kidney hypoplasia and polydactyly, combined exome sequencing and mapping identified a homozygous splice site mutation in PDE6D, encoding a prenyl-binding protein. We found that pde6d depletion in zebrafish leads to renal and retinal developmental anomalies and wild-type but not mutant PDE6D is able to rescue this phenotype. Proteomic analysis identified INPP5E, whose mutations also lead to JS or MORM syndromes, as novel prenyl-dependent cargo of PDE6D. Mutant PDE6D shows reduced binding to INPP5E, which fails to localize to primary cilia in patient fibroblasts and tissues. Furthermore, mutant PDE6D is unable to bind to GTP-bound ARL3, which acts as a cargo-release factor for PDE6D-bound INPP5E. Altogether, these results indicate that PDE6D is required for INPP5E ciliary targeting and suggest a broader role for PDE6D in targeting other prenylated proteins to the cilia. This study identifies PDE6D as a novel JS disease gene and provides the first evidence of prenyl-binding dependent trafficking in ciliopathies.
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DOI：
10.1084/jem.20101597
发表时间：
2010-10-25
期刊：
The Journal of experimental medicine
影响因子：
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作者：
Byun M;Abhyankar A;Lelarge V;Plancoulaine S;Palanduz A;Telhan L;Boisson B;Picard C;Dewell S;Zhao C;Jouanguy E;Feske S;Abel L;Casanova JL
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10.1073/pnas.1210916109
发表时间：
2012-11-27
影响因子：
11.1
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DOI：
10.1126/science.1224026
发表时间：
2012-09-28
期刊：
Science (New York, N.Y.)
影响因子：
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作者：
Bogunovic D;Byun M;Durfee LA;Abhyankar A;Sanal O;Mansouri D;Salem S;Radovanovic I;Grant AV;Adimi P;Mansouri N;Okada S;Bryant VL;Kong XF;Kreins A;Velez MM;Boisson B;Khalilzadeh S;Ozcelik U;Darazam IA;Schoggins JW;Rice CM;Al-Muhsen S;Behr M;Vogt G;Puel A;Bustamante J;Gros P;Huibregtse JM;Abel L;Boisson-Dupuis S;Casanova JL
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Casanova JL
DOI：
10.1084/jem.20110958
发表时间：
2011-08-01
期刊：
The Journal of experimental medicine
影响因子：
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Liu L;Okada S;Kong XF;Kreins AY;Cypowyj S;Abhyankar A;Toubiana J;Itan Y;Audry M;Nitschke P;Masson C;Toth B;Flatot J;Migaud M;Chrabieh M;Kochetkov T;Bolze A;Borghesi A;Toulon A;Hiller J;Eyerich S;Eyerich K;Gulácsy V;Chernyshova L;Chernyshov V;Bondarenko A;Grimaldo RM;Blancas-Galicia L;Beas IM;Roesler J;Magdorf K;Engelhard D;Thumerelle C;Burgel PR;Hoernes M;Drexel B;Seger R;Kusuma T;Jansson AF;Sawalle-Belohradsky J;Belohradsky B;Jouanguy E;Bustamante J;Bué M;Karin N;Wildbaum G;Bodemer C;Lortholary O;Fischer A;Blanche S;Al-Muhsen S;Reichenbach J;Kobayashi M;Rosales FE;Lozano CT;Kilic SS;Oleastro M;Etzioni A;Traidl-Hoffmann C;Renner ED;Abel L;Picard C;Maródi L;Boisson-Dupuis S;Puel A;Casanova JL
通讯作者：
Casanova JL