PUBLICATION
Identification of POLR3B biallelic mutations -associated hypomyelinating leukodystrophy-8 in two siblings
- Authors
- Yang, F., Sun, H., Yang, Y., Wang, Y., Dai, S., Lin, Z., Shen, Y., Liu, H.
- ID
- ZDB-PUB-230119-1
- Date
- 2023
- Source
- Clinical genetics 103(5): 596-602 (Journal)
- Registered Authors
- Keywords
- POLR3B, compound heterozygous variations, hypomyelinating leukodystrophy-8 (HLD8), whole-exome sequencing (WES)
- MeSH Terms
-
- Animals
- Hereditary Central Nervous System Demyelinating Diseases*/genetics
- Humans
- Mutation
- RNA Polymerase III*/genetics
- Siblings
- Zebrafish/genetics
- PubMed
- 36650939 Full text @ Clin. Genet.
Citation
Yang, F., Sun, H., Yang, Y., Wang, Y., Dai, S., Lin, Z., Shen, Y., Liu, H. (2023) Identification of POLR3B biallelic mutations -associated hypomyelinating leukodystrophy-8 in two siblings. Clinical genetics. 103(5):596-602.
Abstract
POLR3B gene encodes the 2nd largest catalytic subunit and affects the function of RNA polymerase III enzymes in transcription. Bi-allelic variants in POLR3B pathogenically cause hypomyelinating leukodystrophy-8 (HLD8). Herein, we recruited a family with two patients, who presented clinically with cerebellar atrophy, intellectual disability, hypogonadotropic hypogonadism, and visual problems. We identified the two affected siblings carrying the compound heterozygous variations (c.165_167del; c.1615G > T) in POLR3B by trio-whole-exome sequencing (trio-WES). The qPCR and western blot showed that both transcriptional and translational levels of the mutation (c.165_167del, p.I55_K56delinsM) were sharply attenuated. Following that, a thorough functional examination of a zebrafish line disrupted for human POLR3B validated the pathogenic effects of the two mutations. Our research broadens the spectrum of HLD8-related pathogenic POLR3B mutations and provides new molecular and animal evidence. This article is protected by copyright. All rights reserved.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping