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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Mutations of POLR3A encoding a catalytic subunit of RNA polymerase pol III cause a recessive hypomyelinating leukodystrophy
American Journal of Human Genetics, Volume 89, No. 3, Year 2011
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Description
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 4H 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 4H fibroblasts and on the autopsied brain of an individual diagnosed with 4H 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 1 (AIMP1). © 2011 The American Society of Human Genetics.
Authors & Co-Authors
Bernard, Geneviève
Canada, Montreal
Centre Universitaire de Santé Mcgill, Hôpital de Montreal Pour Enfants
Canada, Montreal
Institut-hôpital Neurologique de Montréal
Chouery, Éliane
Lebanon, Beirut
Université Saint-joseph de Beyrouth
Putorti, Maria Lisa
Canada, Montreal
Institut-hôpital Neurologique de Montréal
Tétreault, Martine
Canada, Montreal
Institut-hôpital Neurologique de Montréal
Takanohashi, Asako
United States, Washington, D.c.
Childrens National Health System
Carosso, Giovanni
United States, Washington, D.c.
Childrens National Health System
Clément, Isabelle
Canada, Montreal
Institut-hôpital Neurologique de Montréal
Boespflüg-Tanguy, Odile
France, Paris
Hôpital Robert-debré Ap-hp
France, Paris
Université Paris Cité
France, Paris
Inserm
Rodriguez, Diana P.
France, Paris
Inserm
France, Paris
Hôpital Armand-trousseau
France, Paris
Sorbonne Université
Delague, Valeŕie
France, Marseille
Aix Marseille Université
Abou-Ghoch, Joelle
Lebanon, Beirut
Université Saint-joseph de Beyrouth
Jalkh, Nadine
Lebanon, Beirut
Université Saint-joseph de Beyrouth
Dorboz, Imen
France, Paris
Inserm
Fribourg, Sebastien
France, Bordeaux
Université de Bordeaux
Teichmann, Martin
France, Bordeaux
Université de Bordeaux
Megarbane, Andre
Lebanon, Beirut
Université Saint-joseph de Beyrouth
France, Paris
Institut Jérôme Lejeune
Schiffmann, Raphael
United States, Dallas
Baylor University Medical Center at Dallas
Vanderver, Adeline L.
United States, Washington, D.c.
Childrens National Health System
Brais, Bernard
Canada, Montreal
Institut-hôpital Neurologique de Montréal
Statistics
Citations: 219
Authors: 19
Affiliations: 13
Identifiers
Doi:
10.1016/j.ajhg.2011.07.014
ISSN:
00029297
e-ISSN:
15376605
Research Areas
Cancer
Genetics And Genomics