Heterozygous mutations of OTX2 cause severe ocular malformations

Am J Hum Genet. 2005 Jun;76(6):1008-22. doi: 10.1086/430721. Epub 2005 Apr 21.


Major malformations of the human eye, including microphthalmia and anophthalmia, are examples of phenotypes that recur in families yet often show no clear Mendelian inheritance pattern. Defining loci by mapping is therefore rarely feasible. Using a candidate-gene approach, we have identified heterozygous coding-region changes in the homeobox gene OTX2 in eight families with ocular malformations. The expression pattern of OTX2 in human embryos is consistent with the eye phenotypes observed in the patients, which range from bilateral anophthalmia to retinal defects resembling Leber congenital amaurosis and pigmentary retinopathy. Magnetic resonance imaging scans revealed defects of the optic nerve, optic chiasm, and, in some cases, brain. In two families, the mutations appear to have occurred de novo in severely affected offspring, and, in two other families, the mutations have been inherited from a gonosomal mosaic parent. Data from these four families support a simple model in which OTX2 heterozygous loss-of-function mutations cause ocular malformations. Four additional families display complex inheritance patterns, suggesting that OTX2 mutations alone may not lead to consistent phenotypes. The high incidence of mosaicism and the reduced penetrance have implications for genetic counseling.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Animals
  • Anophthalmos / genetics
  • Brain / diagnostic imaging
  • Chromosome Mapping
  • DNA Mutational Analysis
  • Eye Abnormalities / genetics*
  • Eye Abnormalities / pathology*
  • Female
  • Gene Expression Regulation, Developmental
  • Genes, Homeobox
  • Genetic Variation
  • Heterozygote*
  • Homeodomain Proteins / chemistry
  • Homeodomain Proteins / genetics*
  • Humans
  • Magnetic Resonance Imaging
  • Male
  • Mice
  • Models, Genetic
  • Mosaicism
  • Mutation*
  • Open Reading Frames
  • Otx Transcription Factors
  • Pedigree
  • Penetrance
  • Protein Structure, Tertiary
  • Radiography
  • Sequence Analysis, DNA


  • Homeodomain Proteins
  • OTX2 protein, human
  • Otx Transcription Factors
  • Otx2 protein, mouse

Associated data

  • OMIM/106210
  • OMIM/116700
  • OMIM/120200
  • OMIM/177075
  • OMIM/181700
  • OMIM/204000
  • OMIM/206900
  • OMIM/236670
  • OMIM/309700
  • OMIM/607108