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Loss of MAFB Function in Humans and Mice Causes Duane Syndrome, Aberrant Extraocular Muscle Innervation, and Inner-Ear Defects.
journal contribution
posted on 2016-11-29, 15:50 authored by J. G. Park, M. A. Tischfield, A. A. Nugent, L. Cheng, S. A. Di Gioia, W. M. Chan, Gail Maconachie, T. M. Bosley, C. G. Summers, D. G. Hunter, C. D. Robson, Irene Gottlob, E. C. EngleDuane 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.
Funding
Funding support included R01EY12498 (E.C.E.), HD018655 (E.C.E.), and Research to Prevent Blindness Inc. (C.G.S.). J.G.P. is a Howard Hughes Medical Institute Medical Research Fellow, and E.C.E. is a Howard Hughes Medical Institute Investigator.
History
Citation
American Journal of Human Genetics, 2016, 98 (6), pp. 1220-1227Author affiliation
/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/MBSP Non-Medical Departments/Neuroscience, Psychology and BehaviourVersion
- AM (Accepted Manuscript)
Published in
American Journal of Human GeneticsPublisher
Elsevier (Cell Press)issn
0002-9297eissn
1537-6605Acceptance date
2016-03-21Available date
2016-11-29Publisher DOI
Publisher version
http://www.sciencedirect.com/science/article/pii/S0002929716300581Notes
The accession numbers for the variants identified in this study are ClinVar: SCV000265995, SCV000265996, SCV000265997, and SCV000265998.Language
enAdministrator link
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