POLR1C – Treacher Collins syndrome

Treacher Collins syndrome (TCS) is a craniofacial developmental disorder characterized by mandibulofacial dysostosis and cleft palate. While most cases are autosomal dominant due to TCOF1 mutations, biallelic variants in POLR1C have been identified in autosomal recessive TCS (PMID:21131976). POLR1C encodes a shared subunit of RNA polymerases I and III, and its disruption leads to ribosomopathy in neural crest cells.

Initial evidence arose from a cohort study in which three unrelated individuals with TCS carried compound or homozygous loss-of-function POLR1C variants, confirming autosomal recessive inheritance (PMID:21131976). Subsequently, a new family with two affected sisters harboring compound heterozygous POLR1C variants further validated this association, bringing the total to five independent AR probands (PMID:30957429).

Reported disease-causing POLR1C variants include frameshift, nonsense, and splice-site changes, alongside a recurrent missense at Arg279: c.836G>A (p.Arg279Gln).

Segregation analysis shows co-segregation of compound heterozygous variants with TCS in both the consanguineous and non-consanguineous families, with unaffected parents as carriers (PMID:21131976; PMID:30957429).

Functional assays of TCS3-associated missense mutations at Arg279 reveal aberrant localization of POLR1C to lysosomes and inhibited chondrogenic differentiation in ATDC5 cells, consistent with disrupted ribosome biogenesis in craniofacial progenitors (PMID:29567474).

Together, genetic and experimental data support a loss-of-function mechanism for POLR1C in AR TCS. Biallelic POLR1C variants disrupt RNA polymerase I/III function in neural crest cells, leading to mandibulofacial dysostosis. Clinical sequencing of POLR1C is advised in unexplained AR TCS. Key Take-home: Biallelic POLR1C variants cause autosomal recessive Treacher Collins syndrome with variable expressivity and concordant experimental phenotypes, informing diagnostic and counseling strategies.

References

• American journal of medical genetics. Part A • 2019 • Autosomal recessive Treacher Collins syndrome due to POLR1C mutations: Report of a new family and review of the literature. PMID:30957429
• Nature genetics • 2011 • Mutations in genes encoding subunits of RNA polymerases I and III cause Treacher Collins syndrome. PMID:21131976
• Biochemical and biophysical research communications • 2018 • Treacher Collins syndrome 3 (TCS3)-associated POLR1C mutants are localized in the lysosome and inhibits chondrogenic differentiation. PMID:29567474

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