POLR1C基因的隐性突变通过损害RNA聚合酶III的生物合成导致脑白质营养不良。
Recessive mutations in POLR1C cause a leukodystrophy by impairing biogenesis of RNA polymerase III.
作者信息
Thiffault Isabelle, Wolf Nicole I, Forget Diane, Guerrero Kether, Tran Luan T, Choquet Karine, Lavallée-Adam Mathieu, Poitras Christian, Brais Bernard, Yoon Grace, Sztriha Laszlo, Webster Richard I, Timmann Dagmar, van de Warrenburg Bart P, Seeger Jürgen, Zimmermann Alíz, Máté Adrienn, Goizet Cyril, Fung Eva, van der Knaap Marjo S, Fribourg Sébastien, Vanderver Adeline, Simons Cas, Taft Ryan J, Yates John R, Coulombe Benoit, Bernard Geneviève
机构信息
1] Department of Neurology and Neurosurgery, McGill University, Department of Medical Genetics, Montreal Children's Hospital, Research Institute of the McGill University Health Center, 1001 boul Décarie, Montreal, Quebec H4A 3J1, Canada. [2] Service de Génétique, Centre Hospitalier Universitaire Sainte-Justine, 3175 Chemin de la Côte-Sainte-Catherine, Montreal, Quebec H3T1C5, Canada. [3] Center for Pediatric Genomic Medicine, Children's Mercy Hospital, 2420 Pershing Road, Suite 421, Kansas City, Missouri 64108, USA.
Department of Child Neurology, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam 1081 HZ, The Netherlands.
出版信息
Nat Commun. 2015 Jul 7;6:7623. doi: 10.1038/ncomms8623.
A small proportion of 4H (Hypomyelination, Hypodontia and Hypogonadotropic Hypogonadism) or RNA polymerase III (POLR3)-related leukodystrophy cases are negative for mutations in the previously identified causative genes POLR3A and POLR3B. Here we report eight of these cases carrying recessive mutations in POLR1C, a gene encoding a shared POLR1 and POLR3 subunit, also mutated in some Treacher Collins syndrome (TCS) cases. Using shotgun proteomics and ChIP sequencing, we demonstrate that leukodystrophy-causative mutations, but not TCS mutations, in POLR1C impair assembly and nuclear import of POLR3, but not POLR1, leading to decreased binding to POLR3 target genes. This study is the first to show that distinct mutations in a gene coding for a shared subunit of two RNA polymerases lead to selective modification of the enzymes' availability leading to two different clinical conditions and to shed some light on the pathophysiological mechanism of one of the most common hypomyelinating leukodystrophies, POLR3-related leukodystrophy.
一小部分4H（髓鞘形成不足、牙发育不全和低促性腺激素性性腺功能减退）或RNA聚合酶III（POLR3）相关的脑白质营养不良病例，在先前确定的致病基因POLR3A和POLR3B中未检测到突变。在此，我们报告其中8例携带POLR1C隐性突变的病例，POLR1C是一个编码POLR1和POLR3共享亚基的基因，在一些特雷彻·柯林斯综合征（TCS）病例中也发生了突变。通过鸟枪法蛋白质组学和染色质免疫沉淀测序，我们证明POLR1C中导致脑白质营养不良的突变而非TCS突变，会损害POLR3的组装和核输入，但不会影响POLR1，从而导致与POLR3靶基因的结合减少。本研究首次表明，编码两种RNA聚合酶共享亚基的基因中的不同突变会导致酶可用性的选择性改变，进而导致两种不同的临床病症，并为最常见的髓鞘形成不足性脑白质营养不良之一——POLR3相关脑白质营养不良的病理生理机制提供了一些线索。
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