Genetic background has a major effect on the penetrance and severity of craniofacial defects in mice heterozygous for the gene encoding the nucleolar protein Treacle

Dev Dyn. 2004 Apr;229(4):907-14. doi: 10.1002/dvdy.20004.


Treacher Collins syndrome (TCS) is a craniofacial disorder that results from mutations in TCOF1, which encodes the nucleolar protein Treacle. The severity of the clinical features exhibits wide variation and includes hypoplasia of the mandible and maxilla, abnormalities of the external ears and middle ear ossicles, and cleft palate. To determine the in vivo function of Treacle, we previously generated Tcof1 heterozygous mice on a mixed C57BL/6 and 129 background. These mice exhibited a lethal phenotype, which included abnormal development of the maxilla, absence of the eyes and nasal passages, and neural tube defects. Here, we show that placing the mutation onto different genetic backgrounds has a major effect on the penetrance and severity of the craniofacial and other defects. The offspring exhibit markedly variable strain-dependent phenotypes that range from extremely severe and lethal in a mixed CBA/Ca and 129 background, to apparently normal and viable in a mixed BALB/c and 129 background. In the former case, in addition to a profoundly severe craniofacial phenotype, CBA-derived heterozygous mice also exhibited delayed ossification of the long bones, rib fusions, and digit anomalies. The results of our studies indicate that factors in the different genetic backgrounds contribute extensively to the Tcof1 phenotype.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Embryo, Mammalian / metabolism
  • Female
  • Heterozygote
  • High Mobility Group Proteins / genetics
  • High Mobility Group Proteins / metabolism
  • Immunochemistry
  • Intracellular Signaling Peptides and Proteins
  • Male
  • Mandibulofacial Dysostosis / diagnosis
  • Mandibulofacial Dysostosis / genetics*
  • Mice
  • Mice, Inbred Strains
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism
  • Neural Crest / cytology
  • Neural Crest / metabolism
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Penetrance
  • Phosphoproteins / genetics*
  • Phosphoproteins / metabolism
  • SOXE Transcription Factors
  • Transcription Factors


  • High Mobility Group Proteins
  • Intracellular Signaling Peptides and Proteins
  • Neoplasm Proteins
  • Nuclear Proteins
  • Phosphoproteins
  • SOXE Transcription Factors
  • Sox10 protein, mouse
  • TCOF1 protein, human
  • Tcof1 protein, mouse
  • Transcription Factors