Mutation update of transcription factor genes FOXE3, HSF4, MAF, and PITX3 causing cataracts and other developmental ocular defects

Hum Mutat. 2018 Apr;39(4):471-494. doi: 10.1002/humu.23395. Epub 2018 Jan 16.


Mutations in the transcription factor genes FOXE3, HSF4, MAF, and PITX3 cause congenital lens defects including cataracts that may be accompanied by defects in other components of the eye or in nonocular tissues. We comprehensively describe here all the variants in FOXE3, HSF4, MAF, and PITX3 genes linked to human developmental defects. A total of 52 variants for FOXE3, 18 variants for HSF4, 20 variants for MAF, and 19 variants for PITX3 identified so far in isolated cases or within families are documented. This effort reveals FOXE3, HSF4, MAF, and PITX3 to have 33, 16, 18, and 7 unique causal mutations, respectively. Loss-of-function mutant animals for these genes have served to model the pathobiology of the associated human defects, and we discuss the currently known molecular function of these genes, particularly with emphasis on their role in ocular development. Finally, we make the detailed FOXE3, HSF4, MAF, and PITX3 variant information available in the Leiden Online Variation Database (LOVD) platform at,,, and Thus, this article informs on key variants in transcription factor genes linked to cataract, aphakia, corneal opacity, glaucoma, microcornea, microphthalmia, anterior segment mesenchymal dysgenesis, and Ayme-Gripp syndrome, and facilitates their access through Web-based databases.

Keywords: Ayme-Gripp syndrome; LOVD; anterior segment mesenchymal dysgenesis; aphakia; cataract; microcornea.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Cataract / genetics*
  • Eye Abnormalities / genetics*
  • Facies
  • Forkhead Transcription Factors / genetics*
  • Growth Disorders / genetics*
  • Hearing Loss, Sensorineural / genetics*
  • Heat Shock Transcription Factors / genetics*
  • Homeodomain Proteins / genetics*
  • Humans
  • Intellectual Disability / genetics*
  • Mutation
  • Proto-Oncogene Proteins c-maf / genetics*
  • Transcription Factors / genetics*


  • FOXE3 protein, human
  • Forkhead Transcription Factors
  • HSF4 protein, human
  • Heat Shock Transcription Factors
  • Homeodomain Proteins
  • MAF protein, human
  • Proto-Oncogene Proteins c-maf
  • Transcription Factors
  • homeobox protein PITX3

Supplementary concepts

  • Cataracts, Congenital, with Sensorineural Deafness, Down Syndrome-Like Facial Appearance, Short Stature, and Mental Retardation