title: Mutations of POLR3A encoding a catalytic subunit of RNA polymerase Pol III cause a recessive hypomyelinating leukodystrophy.
abstract: 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).
authors.affiliation: Departments of Pediatrics, Neurology and Neurosurgery, Division of Pediatric Neurology, Montreal Children's Hospital, McGill University Heath Center, Montreal, Quebec, Canada. bernard.brais@mcgill.ca
authors.forename: Geneviève
authors.initials: G
authors.lastname: Bernard
authors.forename: Eliane
authors.initials: E
authors.lastname: Chouery
authors.forename: Maria Lisa
authors.initials: ML
authors.lastname: Putorti
authors.forename: Martine
authors.initials: M
authors.lastname: Tétreault
authors.forename: Asako
authors.initials: A
authors.lastname: Takanohashi
authors.forename: Giovanni
authors.initials: G
authors.lastname: Carosso
authors.forename: Isabelle
authors.initials: I
authors.lastname: Clément
authors.forename: Odile
authors.initials: O
authors.lastname: Boespflug-Tanguy
authors.forename: Diana
authors.initials: D
authors.lastname: Rodriguez
authors.forename: Valérie
authors.initials: V
authors.lastname: Delague
authors.forename: Joelle
authors.initials: J
authors.lastname: Abou Ghoch
authors.forename: Nadine
authors.initials: N
authors.lastname: Jalkh
authors.forename: Imen
authors.initials: I
authors.lastname: Dorboz
authors.forename: Sebastien
authors.initials: S
authors.lastname: Fribourg
authors.forename: Martin
authors.initials: M
authors.lastname: Teichmann
authors.forename: André
authors.initials: A
authors.lastname: Megarbane
authors.forename: Raphael
authors.initials: R
authors.lastname: Schiffmann
authors.forename: Adeline
authors.initials: A
authors.lastname: Vanderver
authors.forename: Bernard
authors.initials: B
authors.lastname: Brais
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics*; D005808:Genes, Recessive / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D020279:Hereditary Central Nervous System Demyelinating Diseases / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional / Q000235:genetics; D020125:Mutation, Missense / Q000235:genetics; D011792:Quebec; D012320:RNA Polymerase III / Q000737:chemistry / Q000235:genetics*; D017422:Sequence Analysis, DNA; D014202:Tremor / Q000235:genetics* / Q000473:pathology
chemical_list: D012320:RNA Polymerase III