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Loss of MAFB Function in Humans and Mice Causes Duane Syndrome, Aberrant Extraocular Muscle Innervation, and
Jong G Park1, Max A Tischfield2, Alicia A Nugent3
1Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA; Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA; F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA 02115, USA; Department of Neurology, Harvard Medical School, Boston, MA 02115, USA; Duke University School of Medicine, Durham, NC 27710, USA.
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.
Insights
Duane retraction syndrome (DRS) is caused by MAFB gene mutations affecting eye muscle innervation. This study reveals that abducens nerve underdevelopment is the primary cause of DRS, impacting eye movement.
Area of Science:
- Genetics
- Neuroscience
- Ophthalmology
Background:
- Duane retraction syndrome (DRS) is a congenital disorder affecting eye movement.
- Previous studies suggested abducens nerve issues and aberrant innervation in DRS patients.
Purpose of the Study:
- To investigate the genetic basis of Duane retraction syndrome (DRS).
- To elucidate the developmental mechanisms underlying DRS pathology.
- To correlate MAFB gene mutations with DRS and associated deafness.
Main Methods:
- Genotype-phenotype correlation in human patients with DRS.
- Analysis of Mafb-knockout mouse models.
- Histopathological examination of ocular tissues.
Main Results:
- Identified three heterozygous loss-of-function MAFB mutations causing DRS.
- A dominant-negative MAFB mutation linked to DRS and deafness.
- Mouse models confirmed abducens nerve hypoplasia and aberrant innervation seen in human DRS.
- Disruption of abducens nerve development was shown to cause secondary aberrant innervation.
Conclusions:
- MAFB gene mutations are a significant cause of Duane retraction syndrome.
- A threshold model for MAFB function explains variable disease presentation.
- Primary abducens nerve underdevelopment is the root cause of DRS, leading to aberrant innervation of the lateral rectus muscle.
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