POLR3A and Hypomyelinating Leukodystrophy

POLR3A encodes the largest catalytic subunit of RNA polymerase III and is crucial for the transcription of small noncoding RNAs, including tRNAs and 5S rRNA. Biallelic variants in POLR3A underlie autosomal recessive hypomyelinating leukodystrophy (Pol III-HLD, also known as 4H syndrome) characterized by hypomyelination on MRI, hypodontia, and hypogonadotropic hypogonadism (MONDO:0019046).

Genetic evidence for POLR3A-related leukodystrophy is robust. Initial mapping in French-Canadian families identified 14 recessive POLR3A mutations in 19 individuals with clinical overlap of tremor-ataxia and central hypomyelination (PMID:21855841). Subsequent screening in families with leukodystrophy with oligodontia (LO) and 4H syndrome uncovered additional missense, splice, and frameshift variants, solidifying autosomal recessive inheritance and allelism with related phenotypes.

Case reports expand the variant spectrum and clinical heterogeneity. Two Italian siblings presenting at 19 and 41 years with gait disturbance and amenorrhea carried novel compound heterozygous variants, including c.2554A>G (p.Met852Val) (PMID:32600288). A deep intronic c.645+312C>T variant causing pseudoexon inclusion co-occurs with c.1451G>A (p.Arg484Gln) in a patient manifesting developmental delay and hypodontia (PMID:32483275). A consanguineous Chinese family harbors homozygous c.2300G>T (p.Cys767Phe), with affected siblings exhibiting ataxia, dystonia, and dysarthria (PMID:38561452).

Functional studies demonstrate that pathogenic POLR3A variants impair Pol III transcription. CRISPR-Cas9 introduction of c.2554A>G (p.Met852Val) in human cells reduced BC200 RNA and tRNA levels and decreased MBP expression, indicating hypomorphic Pol III activity (PMID:30898877). Overexpression assays of p.Cys767Phe in oligodendroglial cells revealed failure to enhance Pol III transcription of 5S rRNA and tRNA^Leu-CAA, correlating with reduced myelin basic protein (PMID:38561452).

The mechanism of pathogenicity is loss of function leading to haploinsufficiency of Pol III transcripts essential for myelination. Cellular rescue experiments restore transcript levels only with wild-type POLR3A, confirming the deleterious effect of patient variants.

Integration of genetic and functional data supports a Definitive association between POLR3A and hypomyelinating leukodystrophy. POLR3A variant analysis is clinically useful for diagnosis of late-onset and atypical cases of leukodystrophy, guiding genetic counseling and informing potential therapeutic strategies targeting Pol III function.

Key Take-home: Biallelic POLR3A variants cause autosomal recessive hypomyelinating leukodystrophy through loss of RNA polymerase III activity, with diagnosis supported by genetic testing and functional assays.

References

• American Journal of Human Genetics • 2011 • Mutations of POLR3A encoding a catalytic subunit of RNA polymerase Pol III cause a recessive hypomyelinating leukodystrophy. PMID:21855841
• BMC Neurology • 2020 • A novel POLR3A genotype leads to leukodystrophy type-7 in two siblings with unusually late age of onset. PMID:32600288
• Journal of Human Genetics • 2020 • Identification of a deep intronic POLR3A variant causing inclusion of a pseudoexon derived from an Alu element in Pol III-related leukodystrophy. PMID:32483275
• Scientific Reports • 2024 • Clinical phenotype and genetic function analysis of a family with hypomyelinating leukodystrophy-7 caused by POLR3A mutation. PMID:38561452
• The Journal of Biological Chemistry • 2019 • Leukodystrophy-associated POLR3A mutations down-regulate the RNA polymerase III transcript and important regulatory RNA BC200. PMID:30898877

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