Human Genetic Disorders of Axon Guidance

Engle, Elizabeth C.

doi:10.1101/cshperspect.a001784

Cited by 184 publications

(230 citation statements)

References 161 publications

(173 reference statements)

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“…1 A-C). The arrangement of this "ocular motor" system is conserved across vertebrates; in humans, incorrect development of this pattern of innervation leads to eye movement disorders such as strabismus, which affects 1% of the population, and may result in amblyopia or partial blindness (2). The etiology of these axonal miswiring disorders is poorly understood.…”

mentioning

confidence: 99%

“…In DRS, defects in horizontal eye movements result from incoordination of the medial and lateral recti muscles, which are innervated by the oculomotor and the abducens nerves, respectively (2). Neuroimaging studies suggest that DURS2 may involve absence of the abducens concomitant with aberrant innervation of the LR muscle by the OMN, and/or hypoplasia of both the abducens and oculomotor nerves (4,5).…”

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confidence: 99%

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Axon guidance in the developing ocular motor system and Duane retraction syndrome depends on Semaphorin signaling via alpha2-chimaerin

Ferrario

Baskaran

Clark

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Eye movements depend on correct patterns of connectivity between cranial motor axons and the extraocular muscles. Despite the clinical importance of the ocular motor system, little is known of the molecular mechanisms underlying its development. We have recently shown that mutations in the Chimaerin-1 gene encoding the signaling protein α2-chimaerin (α2-chn) perturb axon guidance in the ocular motor system and lead to the human eye movement disorder, Duane retraction syndrome (DRS). The axon guidance cues that lie upstream of α2-chn are unknown; here we identify candidates to be the Semaphorins (Sema) 3A and 3C, acting via the PlexinA receptors. Sema3A/C are expressed in and around the developing extraocular muscles and cause growth cone collapse of oculomotor neurons in vitro. Furthermore, RNAi knockdown of α2-chn or PlexinAs in oculomotor neurons abrogates Sema3A/C-dependent growth cone collapse. In vivo knockdown of endogenous PlexinAs or α2-chn function results in stereotypical oculomotor axon guidance defects, which are reminiscent of DRS, whereas expression of α2-chn gain-of-function constructs can rescue PlexinA loss of function. These data suggest that α2-chn mediates Sema3-PlexinA repellent signaling. We further show that α2-chn is required for oculomotor neurons to respond to CXCL12 and hepatocyte growth factor (HGF), which are growth promoting and chemoattractant during oculomotor axon guidance. α2-chn is therefore a potential integrator of different types of guidance information to orchestrate ocular motor pathfinding. DRS phenotypes can result from incorrect regulation of this signaling pathway.

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confidence: 99%

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confidence: 99%

Axon guidance in the developing ocular motor system and Duane retraction syndrome depends on Semaphorin signaling via alpha2-chimaerin

Ferrario

Baskaran

Clark

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…A chorionic villus sampling was performed during pregnancy. Postnatal fetal karyotype was 46, XX, isht [4,6] (p15.33, p13.3+; p13.3-,p15.33+). At birth, the baby's Apgar score was 8 at 1 minute, 9 at 5 minute and 10 at 10 minute; her weight was 2540 g, with a 32 cm head circumference.…”

Section: Case Presentationmentioning

confidence: 99%

“…Pregnancy was normal; the mother reported taking only cardio aspirin, she is carrier of balanced translocation isht [4,6]. A chorionic villus sampling was performed during pregnancy.…”

Section: Case Presentationmentioning

confidence: 99%

“…Other hypothesis is that the altered pontine anatomy is related to abnormal migration of pontine nuclei, where the cochlear ganglion cells may not establish normal synaptic connection with cochlear nuclei cells, and subsequently undergo apoptosis. PTCD is considered a syndrome of human genetic disorders of axon guidance, even if its etiology is unknown, but with no genetic cause identified to date [4].…”

Section: Introductionmentioning

confidence: 99%

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Cochlear Implantation in Pontine Tegmental Cap Dysplasia

Meli¹,

Cristofari²

2017

JOENTR

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Pontine tegmental cap dysplasia (PTCD) is a rare disease associated with hearing loss. We present a case of a child with PTCD and Perventricular nodular heterotopia (PNH). PTCD is a brainstem, cerebellar and cranial nerve malformation syndrome characterized by several clinical manifestations. PNH is a condition in which neurons do not migrate properly in the first stage of brain development. Diagnosis of both pathologies is based on the characteristic neuro-image findings. The child was evaluated, in our department, for congenital profound hearing loss, several signs and symptoms emerged during the diagnostic analysis. The clinical data and Neuro-image tests evidenced a diagnosis of PTCD and PHN. Cochlear Implant (CI) therapy for hearing loss in this case is discussed.I treatment in cases with profound hearing loss in PTCD is useful. These patients need a challenging and complex rehabilitative program. An adequate evaluation of clinical and functional responses and a cost-benefit analysis is necessary in the choice of monolateral or bilateral CI. A multidisciplinary and multicenter consensus could be useful in the therapeutic management of similar cases.

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No, Not More Talk About Duane Syndrome

Hoyt¹

2013

JAMA Ophthalmol

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Human Genetic Disorders of Axon Guidance

Cited by 184 publications

References 161 publications

Axon guidance in the developing ocular motor system and Duane retraction syndrome depends on Semaphorin signaling via alpha2-chimaerin

Axon guidance in the developing ocular motor system and Duane retraction syndrome depends on Semaphorin signaling via alpha2-chimaerin

Cochlear Implantation in Pontine Tegmental Cap Dysplasia

No, Not More Talk About Duane Syndrome

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