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

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          Abstract

          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.

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          Author and article information

          Contributors
          Journal
          Am J Hum Genet
          Am. J. Hum. Genet
          American Journal of Human Genetics
          Elsevier
          0002-9297
          1537-6605
          02 June 2016
          12 May 2016
          : 98
          : 6
          : 1220-1227
          Affiliations
          [1 ]Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA
          [2 ]Department of Neurology, Boston Children’s Hospital, Boston, MA 02115, USA
          [3 ]F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Boston, MA 02115, USA
          [4 ]Department of Neurology, Harvard Medical School, Boston, MA 02115, USA
          [5 ]Duke University School of Medicine, Durham, NC 27710, USA
          [6 ]Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA
          [7 ]Ulverscroft Eye Unit, University of Leicester, Leicester LE2 7LX, UK
          [8 ]Department of Neuroscience, Psychology, and Behavior, University of Leicester, Leicester LE2 7LX, UK
          [9 ]Wilmer Eye Institute, Johns Hopkins University, Baltimore, MD 21287, USA
          [10 ]Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, MN 55455, USA
          [11 ]Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA
          [12 ]Department of Ophthalmology, Boston Children’s Hospital, Boston, MA 02115, USA
          [13 ]Department of Ophthalmology, Harvard Medical School, Boston, MA 02115, USA
          [14 ]Department of Radiology, Boston Children’s Hospital, Boston, MA 02115, USA
          [15 ]Department of Radiology, Harvard Medical School, Boston, MA 02115, USA
          [16 ]Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
          Author notes
          [17]

          These authors contributed equally to this work

          Article
          PMC4908193 PMC4908193 4908193 S0002-9297(16)30058-1
          10.1016/j.ajhg.2016.03.023
          4908193
          27181683
          b36f0d66-4338-4b4d-95e9-e5f51cdf5bfb
          © 2016 American Society of Human Genetics.
          History
          : 29 January 2016
          : 21 March 2016
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