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- Title
Identification of POLR3B biallelic mutations‐associated hypomyelinating leukodystrophy‐8 in two siblings.
- Authors
Yang, Fan; Sun, Huaqin; Yang, Yanting; Wang, Yanan; Dai, Siyu; Lin, Ziyuan; Shen, Ying; Liu, Hongqian
- 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.
- Subjects
GENETIC variation; RNA polymerases; SIBLINGS; PATIENTS' families; INTELLECTUAL disabilities
- Publication
Clinical Genetics, 2023, Vol 103, Issue 5, p596
- ISSN
0009-9163
- Publication type
Article
- DOI
10.1111/cge.14300