Clinical phenotype and genetic function analysis of a family with hypomyelinating leukodystrophy-7 caused by POLR3A mutation

• Published in: Scientific reports Vol. 14; no. 1; pp. 7638 - 14
• Main Authors: Ruan, Dan-dan, Ruan, Xing-lin, Wang, Ruo‑li, Lin, Xin-fu, Zhang, Yan-ping, Lin, Bin, Li, Shi-jie, Wu, Min, Chen, Qian, Zhang, Jian-hui, Cheng, Qiong, Zhang, Yi-wu, Lin, Fan, Luo, Jie-wei, Zheng, Zheng, Li, Yun-fei
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-04-2024; Nature Publishing Group; Nature Portfolio
• Subjects: 631/208/199; 631/208/200; 631/208/205; 631/208/2489; 631/208/366; 631/208/730; 631/378; 692/617; Ataxia; Atrophy; Central nervous system; Cognitive ability; Corpus callosum; Dystonia; Female; Genetic analysis; Hereditary Central Nervous System Demyelinating Diseases - genetics; HLD-7; Humanities and Social Sciences; Humans; Hypogonadism; Leukodystrophy; Magnetic resonance imaging; Male; multidisciplinary; Mutants; Mutation; Myelin; Myelination; Neuroimaging; Phenotype; Phenotypes; POLR3-related hypomyelinating leukodystrophy; POLR3A gene; Proteins; RNA polymerase III (Pol III); RNA Polymerase III - genetics; RNA Polymerase III - metabolism; RNA, Transfer; rRNA 18S; rRNA 5S; Science; Science (multidisciplinary); Substantia alba; Transfer RNA; tRNA Leu; HLD-7; Myelination; POLR3-related hypomyelinating leukodystrophy; POLR3A gene; RNA polymerase III (Pol III)
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-024-58452-6

Hypomyelinating leukodystrophy (HLD) is a rare genetic heterogeneous disease that can affect myelin development in the central nervous system. This study aims to analyze the clinical phenotype and genetic function of a family with HLD-7 caused by
POLR3A
mutation. The proband (IV6) in this family mainly showed progressive cognitive decline, dentin dysplasia, and hypogonadotropic hypogonadism. Her three old brothers (IV1, IV2, and IV4) also had different degrees of ataxia, dystonia, or dysarthria besides the aforementioned manifestations. Their brain magnetic resonance imaging showed bilateral periventricular white matter atrophy, brain atrophy, and corpus callosum atrophy and thinning. The proband and her two living brothers (IV2 and IV4) were detected to carry a homozygous mutation of the
POLR3A
(NM_007055.4) gene c. 2300G > T (p.Cys767Phe), and her consanguineous married parents (III1 and III2) were p.Cys767Phe heterozygous carriers. In the constructed
POLR3A
wild-type and p.Cys767Phe mutant cells, it was seen that overexpression of wild-type POLR3A protein significantly enhanced Pol III transcription of 5S rRNA and tRNA Leu-CAA. However, although the mutant POLR3A protein overexpression was increased compared to the wild-type protein overexpression, it did not show the expected further enhancement of Pol III function. On the contrary, Pol III transcription function was frustrated (
POLR3A
,
BC200
, and tRNA Leu-CAA expression decreased), and
MBP
and 18S rRNA expressions were decreased. This study indicates that the
POLR3A
p.Cys767Phe variant caused increased expression of mutated POLR3A protein and abnormal expression of Pol III transcripts, and the mutant POLR3A protein function was abnormal.