Treacher Collins syndrome 3 (TCS3)

Treacher Collins syndrome

Treacher Collins syndrome (TCS) is a disorder of craniofacial development with an estimated incidence of 1:50,000 live births.  The most common findings include downward slanting palpebral fissures and hypoplasia of the zygomatic complex and mandible. Additional findings may include microtia, malformation of the auricles and atresia of the external ear canals, anomalies of the middle ear ossicles resulting in conductive hearing loss, lower lid coloboma with paucity of lid lashes medial to the defect, macrostomia and cleft palate. Treacher Collins syndrome has variable penetrance.  Inheritance may be autosomal dominant or autosomal recessive.

Autosomal dominant Treacher Collins syndrome 1 (TCS1; MIM 154500) and Treacher Collins syndrome 2 (TCS2; MIM 613717) are caused by mutations in the TCOF1 and POLR1D genes, respectively.  Approximately 90% of TCS cases are caused by mutations in treacle, the product of TCOF1.  Treacle is a nucleolar phosphoprotein implicated in ribosomal DNA gene transcription.  Treacle may also be involved with pre-RNA processing within the nucleolus.  Animal studies indicate that haploinsufficiency of Tcof1 results in deficient ribosomal biogenesis in neuroepithelial and neural crest cells. Ribosome deficiency results in p53 stabilization and ultimately causes the activation of proapoptotic genes.  A subset of TCS patients have mutations in POLR1D. This gene encodes a subunit of RNA polymerases I and III.  POLR1D deletion, missense and nonsense mutations have been detected.  The missense mutations described were restricted to the RNA polymerase dimerization domain of the POLR1D gene.

Autosomal recessive Treacher Collins syndrome 3 (TCS3; MIM 248390) is caused by mutations in the POLR1C gene. This gene also encodes a subunit of RNA polymerases I and III. Compound heterozygous POLR1C missense, nonsense, and frameshift mutations have been reported.