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

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.

SUBMITTER: Djordjevic D

PROVIDER: S-EPMC7820722 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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

Djordjevic Djurdja D Pinard Maxime M Gauthier Marie-Soleil MS Smith-Hicks Constance C Hoffman Trevor L TL Wolf Nicole I NI Oegema Renske R van Binsbergen Ellen E Baskin Berivan B Bernard Geneviève G Fribourg Sébastien S Coulombe Benoit B Yoon Grace G

American journal of human genetics 20210101 1

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 d ...[more]

PMID: 33417887

Dataset Information

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

Publications

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

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