Homozygous stop mutation in AHR causes autosomal recessive foveal hypoplasia and infantile nystagmus

Brain. 2019 Jun 1;142(6):1528-1534. doi: 10.1093/brain/awz098.


Herein we present a consanguineous family with three children affected by foveal hypoplasia with infantile nystagmus, following an autosomal recessive mode of inheritance. The patients showed normal electroretinography responses, no signs of albinism, and no anterior segment or brain abnormalities. Upon whole exome sequencing, we identified a homozygous mutation (c.1861C>T;p.Q621*) in the aryl hydrocarbon receptor (AHR) gene that perfectly co-segregated with the disease in the larger family. AHR is a ligand-activated transcription factor that has been intensively studied in xenobiotic-induced toxicity. Further, it has been shown to play a physiological role under normal cellular conditions, such as in immunity, inflammatory response and neurogenesis. Notably, knockout of the Ahr gene in mouse impairs optic nerve myelin sheath formation and results in oculomotor deficits sharing many features with our patients: the eye movement disorder in Ahr-/- mice appears early in development and presents as conjugate horizontal pendular nystagmus. We therefore propose AHR to be a novel disease gene for a new, recessively inherited disorder in humans, characterized by infantile nystagmus and foveal hypoplasia.

Keywords: AHR; consanguinity; foveal hypoplasia; nystagmus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics*
  • Child
  • Electroretinography / methods
  • Female
  • Homozygote*
  • Humans
  • Male
  • Mice
  • Mutation / genetics
  • Nervous System Malformations / genetics
  • Nervous System Malformations / pathology
  • Nystagmus, Congenital / diagnosis
  • Nystagmus, Congenital / genetics*
  • Optic Nerve Hypoplasia / genetics*
  • Optic Nerve Hypoplasia / pathology
  • Pedigree
  • Receptors, Aryl Hydrocarbon / genetics*


  • AHR protein, human
  • Ahr protein, mouse
  • Basic Helix-Loop-Helix Transcription Factors
  • Receptors, Aryl Hydrocarbon