POLR3A – Odontoleukodystrophy

Odontoleukodystrophy (MONDO_0019177), also known as leukodystrophy with oligodontia, is part of the 4H leukodystrophy spectrum characterized by central hypomyelination, hypodontia, and hypogonadotropic hypogonadism. Affected individuals present with diffuse white matter abnormalities on MRI, dental agenesis affecting permanent teeth, and endocrine dysfunction due to gonadotropin deficiency. The clinical and radiological overlap with tremor-ataxia with central hypomyelination (TACH) prompted sequencing of genes within the linked 10q22.3–23.1 interval.

Genetic analysis identified 14 distinct biallelic mutations in the RNA polymerase III catalytic subunit gene POLR3A in 19 unrelated individuals with TACH, 4H syndrome, or odontoleukodystrophy, establishing these phenotypes as allelic (PMID:21855841). The inheritance is autosomal recessive, with no individuals observed to carry two truncating alleles.

Segregation analysis in three multiplex families confirmed co-segregation of POLR3A variants with disease status, encompassing at least eight additional affected relatives beyond probands (PMID:21855841).

The variant spectrum includes missense (e.g., c.92A>G (p.Gln31Arg)), small insertions causing frameshifts, splice-site changes, and premature stop codons. No individuals were homozygous for two nonsense alleles, suggesting hypomorphic alleles contribute to viability. Recurrent variants have not been reported, indicating private mutations in diverse populations.

Functional studies demonstrated significantly decreased POLR3A protein levels in patient fibroblasts and autopsied brain white matter, with preferential loss in oligodendrocyte-rich regions. Reduced Pol III transcript levels, including tRNAs, support a mechanism of hypomorphic Pol III activity leading to impaired protein synthesis in myelinating cells (PMID:21855841).

No conflicting studies have disputed POLR3A’s role in odontoleukodystrophy; all evidence converges on a loss-of-function mechanism with consistent genotype–phenotype correlations.

In summary, biallelic POLR3A variants cause autosomal-recessive odontoleukodystrophy through impaired Pol III transcription and hypomyelination. Genetic testing for POLR3A should be prioritized in patients with hypomyelinating leukodystrophy combined with dental and endocrine anomalies. This association informs diagnostic evaluation, genetic counseling, and potential therapeutic targeting of Pol III function.

Key Take-home: POLR3A loss-of-function underlies odontoleukodystrophy, supporting its inclusion in diagnostic gene panels for hypomyelinating leukodystrophies.

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

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