Large exonic deletions in POLR3B gene cause POLR3-related leukodystrophy.

Mariana Gutierrez,Kether Guerrero,Nicole I Wolf,Isabelle Thiffault,Luan T Tran,William Benko,Marjo S Van Der Knaap,Rosalina M L Van Spaendonk,Gabriel Á Martos-Moreno,Geneviève Bernard

doi:10.1186/s13023-015-0279-9

Abstract

POLR3-related (or 4H) leukodystrophy is an autosomal recessive disorder caused by mutations in POLR3A or POLR3B and is characterized by neurological and non-neurological features. In a small proportion of patients, no mutation in either gene or only one mutation is found. Analysis of the POLR3B cDNA revealed a large deletion of exons 21–22 in one case and of exons 26–27 in another case. These are the first reports of long deletions causing POLR3-related leukodystrophy, suggesting that deletions and duplications in POLR3A or POLR3B should be investigated in patients with a compatible phenotype, especially if one pathogenic variant has been identified.

Highlights

Deoxyribonucleic Acid (DNA)-directed Ribonucleic Acid (RNA) polymerase III (POLR3)-related leukodystrophy is an autosomal recessive disorder caused by mutations in DNA-Directed RNA Polymerase III Subunit A (POLR3A) or DNA-Directed RNA Polymerase III Subunit B (POLR3B) and is characterized by neurological and non-neurological features
Brain Magnetic Resonance Imaging (MRI) shows hypomyelination, i.e. variable signal on T1-weighted images and hyperintense signal of the white matter on T2-weighted images compared to grey matter structures [4], with relative preservation of myelination (i.e. T2hypointensity), of specific structures, with or without cerebellar atrophy and thinning of the corpus callosum [3, 5, 6]. Hypomyelination Hypodontia Hypogonadotropic Hypogonadism (4H) is caused by recessive mutations in POLR3A (MIM#614258) [7,8,9,10] or POLR3B (MIM#614366), encoding respectively the largest and second largest subunits of the DNA-directed RNA polymerase III (POLR3)
POLR3 is responsible for the transcription of transfer RNAs and other small RNAs essential for cellular processes [11]

Summary

Introduction

POLR3-related (or 4H) leukodystrophy is an autosomal recessive disorder caused by mutations in POLR3A or POLR3B and is characterized by neurological and non-neurological features. 4H is caused by recessive mutations in POLR3A (MIM#614258) [7,8,9,10] or POLR3B (MIM#614366), encoding respectively the largest and second largest subunits of the DNA-directed RNA polymerase III (POLR3). Wolf and Geneviève Bernard are co-last authors †Equal contributors 1Departments of Pediatrics, Neurology and Neurosurgery, Montreal Children’s Hospital, McGill University Health Center, 1001 Boulevard Décarie, Montréal, QC H4A 3J1, Canada Full list of author information is available at the end of the article

Results

Conclusion