TY - JOUR
T1 - De novo variants in POLR3B cause ataxia, spasticity, and demyelinating neuropathy
AU - Djordjevic, Djurdja
AU - Pinard, Maxime
AU - Gauthier, Marie-Soleil
AU - Smith-Hicks, Constance
AU - Hoffman, Trevor L.
AU - Wolf, Nicole I.
AU - Oegema, Renske
AU - van Binsbergen, Ellen
AU - Baskin, Berivan
AU - Bernard, Geneviève
AU - Fribourg, S. bastien
AU - Coulombe, Benoit
AU - Yoon, Grace
N1 - Funding Information:
We thank the patients and their families for their participation in the study; this work would not have been possible without their generosity. This study was partly supported by a grant from the Canadian Institutes of Health Research to G.B. and B.C. (CIHR; 201610PJT-377869 ). G.B. has received the CIHR New Investigator Salary Award (2017–2022). B.C. holds a Bell-Bombardier Research Chair awarded by the IRCM. N.I.W. is a member of the European Reference Network for Rare Neurological Disorders (ERN-RND, project ID 739510 ).
Funding Information:
We thank the patients and their families for their participation in the study; this work would not have been possible without their generosity. This study was partly supported by a grant from the Canadian Institutes of Health Research to G.B. and B.C. (CIHR; 201610PJT-377869). G.B. has received the CIHR New Investigator Salary Award (2017?2022). B.C. holds a Bell-Bombardier Research Chair awarded by the IRCM. N.I.W. is a member of the European Reference Network for Rare Neurological Disorders (ERN-RND, project ID 739510).
Publisher Copyright:
© 2020 American Society of Human Genetics
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/1/7
Y1 - 2021/1/7
N2 - 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.
AB - 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.
KW - ataxia
KW - intellectual disability
KW - neuropathy
KW - POLR3B
KW - RNA polymerase III assembly
KW - spasticity
UR - https://www.scopus.com/pages/publications/85098963938
UR - https://www.ncbi.nlm.nih.gov/pubmed/33417887
UR - https://www.scopus.com/pages/publications/85098963938
U2 - 10.1016/j.ajhg.2020.12.002
DO - 10.1016/j.ajhg.2020.12.002
M3 - Article
C2 - 33417887
SN - 0002-9297
VL - 108
SP - 186
EP - 193
JO - American journal of human genetics
JF - American journal of human genetics
IS - 1
ER -