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

• Published in: American journal of human genetics Vol. 89; no. 3; pp. 415 - 423
• Main Authors: Bernard, Geneviève, Chouery, Eliane, Putorti, Maria Lisa, Tétreault, Martine, Takanohashi, Asako, Carosso, Giovanni, Clément, Isabelle, Boespflug-Tanguy, Odile, Rodriguez, Diana, Delague, Valérie, Abou Ghoch, Joelle, Jalkh, Nadine, Dorboz, Imen, Fribourg, Sebastien, Teichmann, Martin, Megarbane, André, Schiffmann, Raphael, Vanderver, Adeline, Brais, Bernard
• Format: Journal Article
• Language: English
• Published: Cambridge, MA Elsevier Inc 09.09.2011; Cell Press; Elsevier
• Subjects: Amino Acid Sequence; Base Sequence; Biological and medical sciences; Brain; Chromosomes, Human, Pair 10 - genetics; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Fundamental and applied biological sciences. Psychology; General aspects. Genetic counseling; Genes, Recessive - genetics; Genetic Predisposition to Disease - genetics; Genetics of eukaryotes. Biological and molecular evolution; Hereditary Central Nervous System Demyelinating Diseases - genetics; Hereditary Central Nervous System Demyelinating Diseases - pathology; Humans; Medical genetics; Medical sciences; Minority & ethnic groups; Models, Molecular; Molecular and cellular biology; Molecular Sequence Data; Mutagenesis, Insertional - genetics; Mutation; Mutation, Missense - genetics; Neurodegeneration; Neurology; Proteins; Quebec; RNA polymerase; RNA Polymerase III - chemistry; RNA Polymerase III - genetics; Sequence Analysis, DNA; Tremor - genetics; Tremor - pathology; Human; Catalytic subunit; Nervous system diseases; Enzyme; Leukodystrophy; Transferases; DNA-directed RNA polymerase; Cerebral disorder; Genetic disease; Nucleotidyltransferases; Central nervous system disease; Recessive character; Genetics; Degenerative disease; Mutation
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1016/j.ajhg.2011.07.014

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).