Loss of MAFB Function in Humans and Mice Causes Duane Syndrome, Aberrant Extraocular Muscle Innervation, and Inner-Ear Defects

Am J Hum Genet. 2016 Jun 2;98(6):1220-1227. doi: 10.1016/j.ajhg.2016.03.023. Epub 2016 May 12.


Duane retraction syndrome (DRS) is a congenital eye-movement disorder defined by limited outward gaze and retraction of the eye on attempted inward gaze. Here, we report on three heterozygous loss-of-function MAFB mutations causing DRS and a dominant-negative MAFB mutation causing DRS and deafness. Using genotype-phenotype correlations in humans and Mafb-knockout mice, we propose a threshold model for variable loss of MAFB function. Postmortem studies of DRS have reported abducens nerve hypoplasia and aberrant innervation of the lateral rectus muscle by the oculomotor nerve. Our studies in mice now confirm this human DRS pathology. Moreover, we demonstrate that selectively disrupting abducens nerve development is sufficient to cause secondary innervation of the lateral rectus muscle by aberrant oculomotor nerve branches, which form at developmental decision regions close to target extraocular muscles. Thus, we present evidence that the primary cause of DRS is failure of the abducens nerve to fully innervate the lateral rectus muscle in early development.

Publication types

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

MeSH terms

  • Animals
  • Duane Retraction Syndrome / etiology*
  • Duane Retraction Syndrome / pathology
  • Embryo, Mammalian / metabolism
  • Embryo, Mammalian / pathology
  • Female
  • Hearing Loss / etiology*
  • Hearing Loss / pathology
  • Humans
  • Labyrinth Diseases / etiology*
  • Labyrinth Diseases / pathology
  • MafB Transcription Factor / genetics*
  • MafB Transcription Factor / physiology*
  • Male
  • Mice
  • Mice, Knockout
  • Oculomotor Muscles / innervation
  • Oculomotor Muscles / pathology*
  • Pedigree


  • MAFB protein, human
  • MafB Transcription Factor
  • Mafb protein, mouse