POLR3A – Wiedemann-Rautenstrauch Syndrome

POLR3A encodes the largest subunit of RNA polymerase III, essential for transcription of small noncoding RNAs. Wiedemann-Rautenstrauch syndrome (WRS; neonatal progeroid syndrome) is an extremely rare autosomal recessive disorder characterized by intrauterine and severe postnatal growth retardation, generalized lipodystrophy, distinctive facial features (triangular face, sparse scalp hair, prominent scalp veins), and dental anomalies including natal teeth (PMID:27612211). Early reports identified a single proband with biallelic truncating variants c.1909+18G>A and c.2617C>T (p.Arg873Ter) in POLR3A, implicating loss-of-function alleles in WRS pathogenesis.

A subsequent multi-patient study confirmed biallelic truncating and splice-site POLR3A variants in seven additional unrelated individuals, bringing the total to eight confirmed cases and replication in 19 families, and firmly establishing autosomal recessive inheritance ([PMID:30414627]). These variants include frameshift (e.g., c.2323_2329del (p.Asn775fs)) and nonsense changes (e.g., c.3291T>G (p.Tyr1097Ter)), as well as canonical splice mutations, all predicted to abolish Pol III function.

Further case reports from diverse populations have expanded the phenotypic spectrum. An Indian patient harbored c.2005C>T (p.Arg669Ter) and c.1771-7C>G in trans, presenting growth delay, sparse hair, and lipoatrophy ([PMID:33559318]). A Russian WRS case carried a novel missense c.3677T>C (p.Leu1226Pro) alongside intronic c.1909+22G>A and c.3337-11T>C variants, with mRNA studies confirming aberrant splicing ([PMID:38397171]). These findings underscore allele heterogeneity and reinforce POLR3A’s role across ethnicities.

Functional investigations demonstrate that WRS-associated variants perturb POLR3A transcript processing. Deep intronic and splice-region alleles (e.g., c.3336G>A, c.3568C>T) cause pseudoexon inclusion or leaky splicing in minigene assays, leading to reduced wild-type transcript levels and premature termination ([PMID:30323018]). In patient fibroblasts, splicing mutations (c.1771-6C>G) and missense alleles (c.3721G>A (p.Val1241Met)) yield decreased expression of Pol III targets (HNRNPH2, ubiquitin B) that is rescued only by wild-type POLR3A overexpression ([PMID:33134517]).

No studies have refuted the POLR3A–WRS association. However, phenotype-genotype correlations remain to be fully delineated, as some variants also underlie hypomyelinating leukodystrophy and hypogonadotropic hypogonadism. The collective data support a loss-of-function mechanism via haploinsufficiency with complete recessive penetrance in WRS.

Key take-home: Biallelic truncating and splice-disrupting POLR3A variants cause autosomal recessive Wiedemann-Rautenstrauch syndrome; genetic testing should include deep intronic regions to capture pathogenic alleles critical for diagnosis and counseling.

References

• American Journal of Human Genetics • 2018 • Bi-allelic POLR3A Loss-of-Function Variants Cause Autosomal-Recessive Wiedemann-Rautenstrauch Syndrome. PMID:30414627
• American Journal of Medical Genetics Part A • 2016 • Neonatal progeriod syndrome associated with biallelic truncating variants in POLR3A. PMID:27612211
• Molecular Genetics & Genomic Medicine • 2018 • Specific combinations of biallelic POLR3A variants cause Wiedemann-Rautenstrauch syndrome. PMID:30323018
• Neurology: Genetics • 2020 • Neurodevelopmental regression, severe generalized dystonia, and metabolic acidosis caused by POLR3A mutations. PMID:33134517
• European Journal of Human Genetics • 2020 • Unique combination and in silico modeling of biallelic POLR3A variants as a cause of Wiedemann-Rautenstrauch syndrome. PMID:32555393

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