Mutations of POLR3A Encoding a Catalytic Subunit of RNA Polymerase Pol III Cause a Recessive Hypomyelinating Leukodystrophy

被引:189
作者
Bernard, Genevieve [1 ,2 ,3 ,4 ]
Chouery, Eliane [5 ]
Putorti, Maria Lisa [1 ]
Tetreault, Martine [1 ]
Takanohashi, Asako [6 ]
Carosso, Giovanni [6 ]
Clement, Isabelle [1 ]
Boespflug-Tanguy, Odile [7 ,8 ,9 ,10 ]
Rodriguez, Diana [10 ,11 ,12 ]
Delague, Valerie [13 ]
Abou Ghoch, Joelle [5 ]
Jalkh, Nadine [5 ]
Dorboz, Imen [9 ,10 ]
Fribourg, Sebastien [14 ]
Teichmann, Martin [14 ]
Megarbane, Andre [5 ,15 ]
Schiffmann, Raphael [16 ]
Vanderver, Adeline [6 ]
Brais, Bernard [1 ]
机构
[1] McGill Univ, Montreal Neurol Inst, Neurogenet Mot Lab, Montreal, PQ H3A 2B4, Canada
[2] McGill Univ, Montreal Childrens Hosp, Ctr Hlth, Div Pediat Neurol,Dept Pediat, Montreal, PQ H3H 1P3, Canada
[3] McGill Univ, Montreal Childrens Hosp, Ctr Hlth, Div Pediat Neurol,Dept Neurol, Montreal, PQ H3H 1P3, Canada
[4] McGill Univ, Montreal Childrens Hosp, Ctr Hlth, Div Pediat Neurol,Dept Neurosurg, Montreal, PQ H3H 1P3, Canada
[5] Univ St Joseph, Fac Med, Unite Genet Med & Lab Associe, INSERM,Unite UMR S 910, Beirut 115076, Riad El Solh, Lebanon
[6] Childrens Natl Med Ctr, Dept Neurol, Washington, DC 20010 USA
[7] Hop Robert Debre, APHP, Reference Ctr Leukodystrophies, F-75019 Paris, France
[8] Univ Paris Diderot, F-75205 Paris 13, France
[9] INSERM, U931, F-63001 Clermont Ferrand, France
[10] INSERM, U676, F-75935 Paris 19, France
[11] Hop Armand Trousseau, AP HP, Serv Neurol Pediat, F-75571 Paris 12, France
[12] Univ Paris 06, UPMC, F-75252 Paris 05, France
[13] Fac Med Timone, INSERM, UMR S 910, F-13385 Marseille, France
[14] Univ Bordeaux, INSERM, IECB, F-33607 Pessac, France
[15] Inst Jerome Lejeune, F-75015 Paris, France
[16] Baylor Res Inst, Inst Metab Dis, Dallas, TX 75226 USA
关键词
HYPOGONADOTROPIC HYPOGONADISM; CELL-GROWTH; TRANSCRIPTION; HYPODONTIA; YEAST; LEUKOENCEPHALOPATHY; ASSOCIATION; SUBCOMPLEX; DISORDERS;
D O I
10.1016/j.ajhg.2011.07.014
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Leukodystrophies are a heterogeneous group of inherited neurodegenerative disorders characterized by abnormal white matter visible by brain imaging. It is estimated that at least 30% to 40% of individuals remain without a precise diagnosis despite extensive investigations. We mapped tremor-ataxia with central hypomyelination (TACH) to 10q22.3-23.1 in French-Canadian families and sequenced candidate genes within this interval. Two missense and one insertion mutations in five individuals with TACH were uncovered in POLR3A, which codes for the largest subunit of RNA polymerase III (Pol III). Because these families were mapped to the same locus as leukodystrophy with oligodontia (LO) and presented clinical and radiological overlap with individuals with hypomyelination, hypodontia and hypogonadotropic hypogonadism (4H) syndrome, we sequenced this gene in nine individuals with 411 and eight with LO. In total, 14 recessive mutations were found in 19 individuals with TACH, 4H, or LO, establishing that these leukodystrophies are allelic. No individual was found to carry two nonsense mutations. Immunoblots on 411 fibroblasts and on the autopsied brain of an individual diagnosed with 414 documented a significant decrease in POLR3A levels, and there was a more significant decrease in the cerebral white matter compared to that in the cortex. Pol III has a wide set of target RNA transcripts, including all nuclear-coded tRNA. We hypothesize that the decrease in POLR3A leads to dysregulation of the expression of certain Pol III targets and thereby perturbs cytoplasmic protein synthesis. This type of broad alteration in protein synthesis is predicted to occur in other leukoencephalopathies such as hypomyelinating leukodystrophy-3, caused by mutations in aminoacyl-tRNA synthetase complex-interacting multifunctional protein I (AIMP1).
引用
收藏
页码:415 / 423
页数:9
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