De novo variants in POLR3B cause ataxia, spasticity, and demyelinating neuropathy

Djurdja Djordjevic; Maxime Pinard; Marie-Soleil Gauthier; Constance Smith-Hicks; Trevor L Hoffman; Nicole I Wolf; Renske Oegema; Ellen van Binsbergen; Berivan Baskin; Geneviève Bernard; Sébastien Fribourg; Benoit Coulombe; Grace Yoon

doi:10.1016/j.ajhg.2020.12.002

De novo variants in POLR3B cause ataxia, spasticity, and demyelinating neuropathy

Am J Hum Genet. 2021 Jan 7;108(1):186-193. doi: 10.1016/j.ajhg.2020.12.002.

Affiliations

¹ Division of Neurology, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON M5G 1X8, Canada.
² Translational Proteomics Research Unit, Institut de Recherches Cliniques de Montréal, Montréal, QC H2W 1R7, Canada.
³ Division of Neurogenetics, Department of Neurology, Kennedy Krieger Institute and Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
⁴ Southern California Kaiser Permanente Medical Group, Anaheim, CA, 92801, USA.
⁵ Department of Child Neurology, Amsterdam Leukodystrophy Center, Emma Children's Hospital, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, and Amsterdam Neuroscience, 1081 HV Amsterdam, the Netherlands.
⁶ Department of Genetics, University Medical Center Utrecht, 3584 EA Utrecht, the Netherlands.
⁷ GeneDx, Gaithersburg, MD, 20877, USA.
⁸ Departments of Neurology and Neurosurgery, Pediatrics and Human Genetics, McGill University, Department of Specialized Medicine, Division of Medical Genetics, McGill University Health Center, and Child Health and Human Development Program, Research Institute of the McGill University Health Centre, Montréal, QC, H4A 3J1, Canada.
⁹ Université de Bordeaux, INSERM U1212, CNRS 5320, Bordeaux, 33076, France.
¹⁰ Translational Proteomics Research Unit, Institut de Recherches Cliniques de Montréal, Montréal, QC H2W 1R7, Canada; Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, QC, H3C 3J7, Canada.
¹¹ Division of Neurology, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON M5G 1X8, Canada; Division of Clinical and Metabolic Genetics, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, M5G 1X8, Canada. Electronic address: [email protected].

Abstract

POLR3B encodes the second-largest catalytic subunit of RNA polymerase III, an enzyme involved in transcription. Bi-allelic pathogenic variants in POLR3B are a well-established cause of hypomyelinating leukodystrophy. We describe six unrelated individuals with de novo missense variants in POLR3B and a clinical presentation substantially different from POLR3-related leukodystrophy. These individuals had afferent ataxia, spasticity, variable intellectual disability and epilepsy, and predominantly demyelinating sensory motor peripheral neuropathy. Protein modeling and proteomic analysis revealed a distinct mechanism of pathogenicity; the de novo POLR3B variants caused aberrant association of individual enzyme subunits rather than affecting overall enzyme assembly or stability. We expand the spectrum of disorders associated with pathogenic variants in POLR3B to include a de novo heterozygous POLR3B-related disorder.

Keywords: POLR3B; RNA polymerase III assembly; ataxia; intellectual disability; neuropathy; spasticity.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Ataxia / genetics*
Cerebellar Ataxia / genetics
Child
Child, Preschool
Female
Genes, Recessive / genetics
Hereditary Central Nervous System Demyelinating Diseases / genetics*
Heterozygote
Humans
Male
Mutation, Missense / genetics
Proteomics / methods
RNA Polymerase III / genetics*
Young Adult

Substances

POLR3B protein, human
RNA Polymerase III

Grants and funding

CIHR/Canada