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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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posted on 29.11.2016, 15:50 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. Engle
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.

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. 1220-1227

Author affiliation

/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/MBSP Non-Medical Departments/Neuroscience, Psychology and Behaviour

Version

AM (Accepted Manuscript)

Published in

American Journal of Human Genetics

Publisher

Elsevier (Cell Press)

issn

0002-9297

eissn

1537-6605

Acceptance date

21/03/2016

Available date

29/11/2016

Publisher version

http://www.sciencedirect.com/science/article/pii/S0002929716300581

Notes

The accession numbers for the variants identified in this study are ClinVar: SCV000265995, SCV000265996, SCV000265997, and SCV000265998.

Language

en

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