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

Park, Jong G.; Tischfield, Max A.; Nugent, Alicia A.; Cheng, Long; Gioia, Silvio Alessandro Di; Chan, Wai Man; Maconachie, Gail; Bosley, Thomas M.; Summers, C. Gail; Hunter, David G.; Robson, Caroline D.; Gottlob, Irène; Engle, Elizabeth C.

doi:10.1016/j.ajhg.2016.03.023

Cited by 69 publications

(87 citation statements)

References 35 publications

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“…The primary DRS phenotype, however, was recently shown to arise from developmental absence of the abducens nerve and the subsequent ectopic innervation of its lateral rectus muscle target by the oculomotor nerve (24). These data suggest that CHN1 mutations are more likely to cause primary defects in abducens rather than oculomotor nerve development.…”

Section: Introductionmentioning

confidence: 52%

“…We report that CHN1 mutations identified in human patients, when modeled in the mouse, cause primary abducens nerve stalling within the mesenchyme, preventing the abducens nerve from contacting the lateral rectus muscle. Within the orbit, the oculomotor nerve sends stereotypical aberrant branches to misinnervate the lateral rectus, which has recently been shown to also occur secondarily to the absence of abducens motor neurons (24). Together, these studies strongly indicate that DRS results from a primary developmental insult to the abducens nucleus or nerve that prevents its innervation of the lateral rectus.…”

Section: Chn1mentioning

confidence: 59%

“…Thus, we investigated whether DRS-mutant Chn1 in mouse alters oculomotor or trochlear nerve development. Notably, while we found aberrant innervation by the oculomotor nerve of the lateral rectus muscle within the orbit secondary to absence of the abducens nerve (Figure 2, A and B) (24), its trajectory was otherwise indistinguishable from WT (Figure 1, D, E, G, and H, and Supplemental Videos 1 and 2). Thus, our results with endogenous mutant Chn1 expression differ from the reported oculomotor stalling that follows overexpression of mutant Chn1 in chick and zebrafish (3,18,23).…”

Section: Neuronal and Mesenchymal Epha4 Conditional Knockouts Reveal mentioning

confidence: 97%

“…-GFP-positive mouse embryos from the indicated genetic crosses were prepared as previously described (24 (11,16,18); it will be of future interest to determine the contribution of these and other guidance pathways in Chn1 KI/KI phenotypes. Third, distinct receptor composition in different neuronal subtypes may mediate integration of different ligands that act through α2-chimaerin to yield different phenotypes.…”

Section: Mnmentioning

confidence: 99%

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Mutant α2-chimaerin signals via bidirectional ephrin pathways in Duane retraction syndrome

Nugent¹,

Park²,

Wei³

et al. 2017

Journal of Clinical Investigation

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Duane retraction syndrome (DRS) is the most common form of congenital paralytic strabismus in humans and can result from α2-chimaerin (CHN1) missense mutations. We report a knockin α2-chimaerin mouse (Chn1 abducens neurons use bidirectional ephrin signaling via mutant α2-chimaerin to direct growth, while cervical spinal neurons use only ephrin forward signaling, and trochlear neurons do not use ephrin signaling. These findings reveal a role for ephrin bidirectional signaling upstream of mutant α2-chimaerin in DRS, which may contribute to the selective vulnerability of abducens motor neurons in this disorder.

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Section: Introductionmentioning

confidence: 52%

Section: Chn1mentioning

confidence: 59%

Section: Neuronal and Mesenchymal Epha4 Conditional Knockouts Reveal mentioning

confidence: 97%

Section: Mnmentioning

confidence: 99%

See 2 more Smart Citations

Mutant α2-chimaerin signals via bidirectional ephrin pathways in Duane retraction syndrome

Nugent¹,

Park²,

Wei³

et al. 2017

Journal of Clinical Investigation

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“…Mafb was first described as a gene related to musculoaponeurotic fibrosarcoma, and now is known to be the responsible gene for the Kreisler mutant ( kr/kr ) and Duane syndrome, characterized by inner ear defects and segmentation abnormalities in rhombomeres during early embryogenesis [49, 50]. Yu et al indicated that Mafb works downstream of Gata3 and contributed to synaptogenesis between IHCs and type I PANs [51].…”

Section: Resultsmentioning

confidence: 99%

Dynamic Expression of Sox2, Gata3, and Prox1 during Primary Auditory Neuron Development in the Mammalian Cochlea

2017

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Primary auditory neurons (PANs) connect cochlear sensory hair cells in the mammalian inner ear to cochlear nucleus neurons in the brainstem. PANs develop from neuroblasts delaminated from the proneurosensory domain of the otocyst and keep maturing until the onset of hearing after birth. There are two types of PANs: type I, which innervate the inner hair cells (IHCs), and type II, which innervate the outer hair cells (OHCs). Glial cells surrounding these neurons originate from neural crest cells and migrate to the spiral ganglion. Several transcription factors are known to regulate the development and differentiation of PANs. Here we systematically examined the spatiotemporal expression of five transcription factors: Sox2, Sox10, Gata3, Mafb, and Prox1 from early delamination at embryonic day (E) 10.5 to adult. We found that Sox2 and Sox10 were initially expressed in the proneurosensory cells in the otocyst (E10.5). By E12.75 both Sox2 and Sox10 were downregulated in the developing PANs; however, Sox2 expression transiently increased in the neurons around birth. Furthermore, both Sox2 and Sox10 continued to be expressed in spiral ganglion glial cells. We also show that Gata3 and Prox1 were first expressed in all developing neurons, followed by a decrease in expression of Gata3 and Mafb in type I PANs and Prox1 in type II PANs as they matured. Moreover, we describe two subtypes of type II neurons based on Peripherin expression. These results suggest that Sox2, Gata3 and Prox1 play a role during neurogenesis as well as maturation of the PANs.

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Clinical and molecular cytogenetic studies of five new patients with 20q11q12 deletion and review of the literature: Proposition of two critical regions

Bensaid,

Bendahmane,

Loddo

et al. 2024

American J of Med Genetics Pt A

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Deletions of the long arm of chromosome 20 (20q) are rare, with only 16 reported patients displaying a proximal interstitial 20q deletion. A 1.62 Mb minimal critical region at 20q11.2, encompassing three genes GDF5, EPB41L1, and SAMHD1, is proposed to be responsible for this syndrome. The leading clinical features include growth retardation, intractable feeding difficulties with gastroesophageal reflux, hypotonia and psychomotor developmental delay. Common facial dysmorphisms including triangular face, hypertelorism, and hypoplastic alae nasi were additionally reported. Here, we present the clinical and molecular findings of five new patients with proximal interstitial 20q deletions. We analyzed the phenotype and molecular data of all previously reported patients with 20q11.2q12 microdeletions, along with our five new cases. Copy number variation analysis of patients in our cohort has enabled us to identify the second critical region in the 20q11.2q12 region and redefine the first region that is initially identified. The first critical region spans 359 kb at 20q11.2, containing six MIM genes, including two disease‐causing genes, GDF5 and CEP250. The second critical region spans 706 kb at 20q12, encompassing four MIM genes, including two disease‐causing genes, MAFB and TOP1. We propose GDF5 to be the primary candidate gene generating the phenotype of patients with 20q11.2 deletions. Moreover, we hypothesize TOP1 as a potential candidate gene for the second critical region at 20q12. Of note, we cannot exclude the possibility of a synergistic role of other genes involved in the deletion, including a contiguous gene deletion syndrome or position effect affecting both critical regions. Further studies focusing on patients with proximal 20q deletions are required to support our hypothesis.

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

Cited by 69 publications

References 35 publications

Mutant α2-chimaerin signals via bidirectional ephrin pathways in Duane retraction syndrome

Mutant α2-chimaerin signals via bidirectional ephrin pathways in Duane retraction syndrome

Dynamic Expression of Sox2, Gata3, and Prox1 during Primary Auditory Neuron Development in the Mammalian Cochlea

Clinical and molecular cytogenetic studies of five new patients with 20q11q12 deletion and review of the literature: Proposition of two critical regions

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