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The Journal of Clinical Investigation May 2017Duane retraction syndrome (DRS) is the most common form of congenital paralytic strabismus in humans and can result from α2-chimaerin (CHN1) missense mutations. We...
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 (Chn1KI/KI) that models DRS. Whole embryo imaging of Chn1KI/KI mice revealed stalled abducens nerve growth and selective trochlear and first cervical spinal nerve guidance abnormalities. Stalled abducens nerve bundles did not reach the orbit, resulting in secondary aberrant misinnervation of the lateral rectus muscle by the oculomotor nerve. By contrast, Chn1KO/KO mice did not have DRS, and embryos displayed abducens nerve wandering distinct from the Chn1KI/KI phenotype. Murine embryos lacking EPH receptor A4 (Epha4KO/KO), which is upstream of α2-chimaerin in corticospinal neurons, exhibited similar abducens wandering that paralleled previously reported gait alterations in Chn1KO/KO and Epha4KO/KO adult mice. Findings from Chn1KI/KI Epha4KO/KO mice demonstrated that mutant α2-chimaerin and EphA4 have different genetic interactions in distinct motor neuron pools: 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.
Topics: Animals; Cerebral Cortex; Chimerin 1; Duane Retraction Syndrome; Embryo, Mammalian; Humans; Mice; Mice, Knockout; Motor Neurons; Receptor, EphA4; Signal Transduction; Spinal Cord
PubMed: 28346224
DOI: 10.1172/JCI88502 -
Ophthalmic Genetics Oct 2021: Duane retraction syndrome and arthrogryposis multiplex congenita have an incidence of approximately 1:1500-1:3000 live births. However, the association of these two...
A 7-year old female with arthrogryposis multiplex congenita, Duane retraction syndrome, and Marcus Gunn phenomenon due to a ZC4H2 gene mutation: a clinical presentation of the Wieacker-Wolff syndrome.
: Duane retraction syndrome and arthrogryposis multiplex congenita have an incidence of approximately 1:1500-1:3000 live births. However, the association of these two entities with a Marcus-Gunn might be a rare and, until now, under-recognized clinical presentation of the Wieacker-Wolff Syndrome.: We report a 7-year-old female with dysmorphic features, global developmental delay, arthrogryposis multiplex congenita (AMC), Duane retraction syndrome (DRS), and unilateral Marcus Gunn jaw winking.: Whole Exome Sequencing showed a de novo premature stop codon in ZC4H2. Extensive genetic and metabolic work was negative otherwise and Brain MRI showed delayed non-specific myelination abnormalities. She continues to have significant delays but does not have regression, seizures or other neurological complications. She has required a multidisciplinary approach for the management of her multiple contractures.: This case confirms ZC4H2 as a cause of syndromic DRS and extends the ZC4H2 phenotype to include Marcus Gunn jaw winking.
Topics: Apraxias; Arthrogryposis; Blepharoptosis; Child; Codon, Nonsense; Contracture; Duane Retraction Syndrome; Female; Genetic Diseases, X-Linked; Heart Defects, Congenital; Humans; Intracellular Signaling Peptides and Proteins; Jaw Abnormalities; Magnetic Resonance Imaging; Muscular Atrophy; Mutation; Nervous System Diseases; Nuclear Proteins; Ophthalmoplegia; Reflex, Abnormal; Exome Sequencing
PubMed: 33949289
DOI: 10.1080/13816810.2021.1923040 -
Kidney International Aug 2018Focal segmental glomerulosclerosis (FSGS) is a leading cause of end-stage renal disease in children and adults. Genetic factors significantly contribute to early-onset...
Focal segmental glomerulosclerosis (FSGS) is a leading cause of end-stage renal disease in children and adults. Genetic factors significantly contribute to early-onset FSGS, but the etiologies of most adult cases remain unknown. Genetic studies of monogenic syndromic FSGS exhibiting extra-renal manifestations have uncovered an unexpected biological role for genes in the development of both podocytes and other cellular lineages. To help define these roles, we studied two unrelated families with FSGS associated with Duane Retraction Syndrome, characterized by impaired horizontal eye movement due to cranial nerve malformation. All four affected individuals developed FSGS and Duane Retraction Syndrome in their first to second decade of life, manifested as restricted abduction together with globe retraction and narrowed palpebral fissure on attempted adduction. Hypoplasia of the abducens nerves and hearing impairment occurred in severely affected individuals. Genetic analyses revealed that affected individuals harbor a rare heterozygous substitution (p.Leu239Pro) in MAFB, a leucine zipper transcription factor. Luciferase assays with cultured monocytes indicated that the substitution significantly reduced transactivation of the F4/80 promoter, the known MAFB recognition element. Additionally, immunohistochemistry indicated reduced MAFB expression in the podocytes of patients. Structural modeling suggested that the p.Leu239Pro substitution in the DNA-binding domain possibly interferes with the stability of the adjacent zinc finger. Lastly, podocytes in neonatal mice with p.Leu239Pro displayed impaired differentiation. Thus, MAFB mutations impair development and/or maintenance of podocytes, abducens neurons and the inner ear. The interactions between MAFB and regulatory elements in these developing organs are likely highly specific based on spatiotemporal requirements.
Topics: Adolescent; Adult; Age of Onset; Amino Acid Substitution; Animals; Child; Duane Retraction Syndrome; Female; Genetic Testing; Glomerulosclerosis, Focal Segmental; Heterozygote; Humans; Kidney Failure, Chronic; MafB Transcription Factor; Male; Mice; Mutation; Podocytes; Protein Domains; Sequence Homology, Amino Acid; Young Adult
PubMed: 29779709
DOI: 10.1016/j.kint.2018.02.025 -
The Journal of Craniofacial Surgery Sep 2019Oculo-auriculo-fronto-nasal syndrome (OAFNS) is a rare anomaly characterized by features overlapping those of frontonasal dysplasia (FND) and the...
Oculo-auriculo-fronto-nasal syndrome (OAFNS) is a rare anomaly characterized by features overlapping those of frontonasal dysplasia (FND) and the oculo-auriculo-vertebral spectrum (OAVS). The FND features malformation of frontonasal process-derived structures, characterized by anomalies in the central portion of the face. The OAVS is characterized by developmental anomalies of the first and second pharyngeal arches. The OAFNS is a condition with clinical features of both FND and OAVS.Here, the authors present the case of a male with OAFNS who not only exhibited typical OAFNS symptoms but also a dysplastic bony structure that bridged the anterior nasal spine and inferior nasal bones, and unilateral type 3 Duane retraction syndrome (absence of right-eye abduction). Abnormal nasal bones are characteristic of OAFNS; such abnormalities are absent from FND and OAVS. The authors reduced the dysplastic nasal bony structure via open external rhinoplasty, followed by lateral nasal osteotomy when he was 16 years of age. The nasal dorsum appeared natural after surgery and he was satisfied with the result.
Topics: Adolescent; Craniofacial Abnormalities; Duane Retraction Syndrome; Face; Humans; Hyperplasia; Male; Nasal Bone; Nose
PubMed: 31756883
DOI: 10.1097/SCS.0000000000005636 -
Taiwan Journal of Ophthalmology 2017To report the surgical effect in upshoot of Duane retraction syndrome (DRS) with corecession of horizontal rectus muscles with or without Y-splitting.
PURPOSE
To report the surgical effect in upshoot of Duane retraction syndrome (DRS) with corecession of horizontal rectus muscles with or without Y-splitting.
PATIENTS AND METHODS
A retrospective chart review of six patients of DRS received muscle surgeries for upshoot in adducted position was performed.
RESULTS
From 1994 to 2010, six Duane patients received muscle surgeries for upshoots of lesion eye in adduction. Their age of receiving surgery ranged from 5 to 41 years. Four of the patients were male, and five had their left eye involved. Three underwent recession of ipsilateral medial and lateral rectus (LR) muscles, and the other three also received Y-splitting of LR muscle when recession. One of the patients that received Y-splitting showed mild hypertropia at down gaze postoperatively, and another one had little improvement of exotropia at the primary position. All patients showed improvement of their upshoots and lid fissure narrowing in adduction as well as face turn.
CONCLUSION
Postoperative improvements in abnormal head posture and upshoots were achieved with corecession of horizontal muscles with or without Y-splitting. Although Y-splitting of the LR muscle is an effective surgery, it might cause undesired complications.
PubMed: 29018752
DOI: 10.4103/tjo.tjo_23_17 -
The Journal of Neuroscience : the... Aug 2021A precise sequence of axon guidance events is required for the development of the ocular motor system. Three cranial nerves grow toward, and connect with, six...
A precise sequence of axon guidance events is required for the development of the ocular motor system. Three cranial nerves grow toward, and connect with, six extraocular muscles in a stereotyped pattern, to control eye movements. The signaling protein alpha2-chimaerin (α2-CHN) plays a pivotal role in the formation of the ocular motor system; mutations in , encoding α2-CHN, cause the human eye movement disorder Duane Retraction Syndrome (DRS). Our research has demonstrated that the manipulation of α2-chn signaling in the zebrafish embryo leads to ocular motor axon wiring defects, although the signaling cascades regulated by α2-chn remain poorly understood. Here, we demonstrate that several cytoskeletal regulatory proteins-collapsin response mediator protein 2 (CRMP2; encoded by the gene ), stathmin1, and stathmin 2-bind to α2-CHN. , , and especially are expressed by ocular motor neurons. We find that the manipulation of and of in zebrafish larvae leads to defects in both the axon wiring of the ocular motor system and the optokinetic reflex, impairing horizontal eye movements. Knockdowns of these molecules in zebrafish larvae of either sex caused axon guidance phenotypes that included defasciculation and ectopic branching; in some cases, these phenotypes were reminiscent of DRS. knock-down phenotypes were rescued by the overexpression of CRMP2 and STMN1, suggesting that these proteins act in the same signaling pathway. These findings suggest that CRMP2 and stathmins signal downstream of α2-CHN to orchestrate ocular motor axon guidance and to control eye movements. The precise control of eye movements is crucial for the life of vertebrate animals, including humans. In humans, this control depends on the arrangement of nerve wiring of the ocular motor system, composed of three nerves and six muscles, a system that is conserved across vertebrate phyla. Mutations in the protein alpha2-chimaerin have previously been shown to cause eye movement disorders (squint) and axon wiring defects in humans. Our recent work has unraveled how alpha2-chimaerin coordinates axon guidance of the ocular motor system in animal models. In this article, we demonstrate key roles for the proteins CRMP2 and stathmin 1/2 in the signaling pathway orchestrated by alpha2-chimaerin, potentially giving insight into the etiology of eye movement disorders in humans.
Topics: Animals; Axon Guidance; Chimerin 1; Duane Retraction Syndrome; Eye Movements; Motor Neurons; Nerve Tissue Proteins; Oculomotor Muscles; Signal Transduction; Stathmin; Zebrafish; Zebrafish Proteins
PubMed: 34168008
DOI: 10.1523/JNEUROSCI.0983-19.2021 -
Genes Oct 2021Biallelic truncating variants result in cilia dysfunction and have been reported in four infants with Joubert syndrome and orofaciodigital syndrome type VI,...
Biallelic truncating variants result in cilia dysfunction and have been reported in four infants with Joubert syndrome and orofaciodigital syndrome type VI, respectively. We report here on three adult siblings, 18 to 40 years of age, homozygous for the known c.354_357delinsCACTC (p.Gln118Hisfs*20) variant. Detailed clinical examinations were performed including ocular and gait analyses, skeletal- and neuroimaging. All three patients presented with neurological and oculomotor symptoms since birth and mild skeletal dysplasia in infancy resulting in characteristic gait abnormalities. We document mild skeletal dysplasia, abnormal gait with increased hip rotation and increased external foot rotation, ataxia, variable polydactyly, ocular Duane syndrome, progressive ophthalmoplegia, nystagmus, situs inversus of the retinal vessels, olfactory bulb aplasia, and corpus callosal dysgenesis as novel features in -ciliopathy. We show that intellectual disability is mild to moderate and retinal, renal and liver function is normal in these affected adults. Our study thus expands the -related Joubert syndrome to a mainly neurological and skeletal ciliopathy phenotype with predominant oculomotor dysfunction but otherwise stable outcome in adults. Diagnosis of -related disorder was impeded by segregation of multiple neurogenetic disorders in the same family, highlighting the importance of extended clinical and genetic studies in families with complex phenotypes.
Topics: Abnormalities, Multiple; Adolescent; Adult; Cerebellum; Ciliopathies; Consanguinity; Cytoskeletal Proteins; Duane Retraction Syndrome; Eye Abnormalities; Female; Humans; Kidney Diseases, Cystic; Male; Nervous System Malformations; Phenotype; Retina; Saudi Arabia; Siblings; Young Adult
PubMed: 34828254
DOI: 10.3390/genes12111648 -
European Journal of Medical Genetics Feb 2016Okihiro syndrome, Duane-radial ray syndrome or acro-reno-ocular syndrome (OMIM #607323) are alternative denominations describing an extremely variable condition,...
Okihiro syndrome, Duane-radial ray syndrome or acro-reno-ocular syndrome (OMIM #607323) are alternative denominations describing an extremely variable condition, characterized by several radial defects of the upper limbs associated with Duane anomaly. It is a rare autosomal dominant disorder determined by variants in the SALL4 gene which encodes a transcription factor with eight zinc finger motifs. Here we report a novel heterozygous frameshift variant, c.410dupG, present in a Brazilian family. The five affected individuals exhibit a broad spectrum of phenotypes, ranging from the severe one presented by the index case (grossly shortened and deformed forearm, markedly hypoplastic and appendicular thumb, malformed right foot and ear malformation), to the less conspicuous condition presented by his near relatives (usually only triphalangeal or hypoplastic thumbs, sometimes associated with ulnar deviation); Duane's anomaly, however, was not observed in any of the affected family members. The c.410dupG variant is predicted to result in the translation of a truncated protein with 180 amino acid residues, lacking seven of the eight zinc finger motifs, with the same size of the predicted products of the already reported c.496dupC variant, described in two unrelated cases. However, the phenotypes observed in the three families (the one here reported and other two with c.496dupC variant) are very different. The analysis of cases so far published does not permit to establish a clear or direct genotype-phenotype correlation, but the three more severe foot malformation cases are due to variants predicted to encode truncated proteins lacking seven ZFMs. This might indicate a possible correlation between foot malformation and reduced size of the protein, suggesting that the nonsense-mediated-decay mechanism might not be so effective as to eliminate all SALL4 variants harboring premature termination codons.
Topics: Brazil; DNA Mutational Analysis; Duane Retraction Syndrome; Female; Frameshift Mutation; Humans; Male; Pedigree; Penetrance; Transcription Factors
PubMed: 26791099
DOI: 10.1016/j.ejmg.2015.12.015 -
Indian Journal of Ophthalmology Aug 2014
Topics: Accommodation, Ocular; Duane Retraction Syndrome; Esotropia; Eye Movements; Female; Humans; Male; Oculomotor Muscles; Ophthalmologic Surgical Procedures; Vision, Binocular
PubMed: 25230971
DOI: 10.4103/0301-4738.141069 -
Scientific Reports Oct 2020Duane retraction syndrome (DRS) is a neuromuscular dysfunction of the eyes. Although many causative genes of DRS have been identified in Europe and the United States,...
Duane retraction syndrome (DRS) is a neuromuscular dysfunction of the eyes. Although many causative genes of DRS have been identified in Europe and the United States, few reports have been published in regard to Chinese DRS. The aim of the present study was to explore the genetic defect of DRS in a Chinese family. Exome sequencing was used to identify the disease-causing gene for the two affected family members. Ophthalmic and physical examinations, as well as genetic screenings for variants in chimerin 1 (CHN1), were performed for all family members. Functional analyses of a CHN1 variant in 293T cells included a Rac-GTP activation assay, α2-chimaerin translocation assay, and co-immunoprecipitation assay. Genetic analysis revealed a NM_001822.7: c.637T > G variant in the CHN1 gene, which resulted in the substitution of a highly conserved C1 domain with valine at codon 213 (NP_001813.1: p.(Phe213Val)) (ClinVar Accession Number: SCV001335305). In-silico analysis revealed that the p.(Phe213Val) substitution affected the protein stability and connections among the amino acids of CHN1 in terms of its tertiary protein structure. Functional studies indicated that the p.(Phe213Val) substitution reduced Rac-GTP activity and enhanced membrane translocation in response to phorbol-myristoyl acetate (PMA). Together with previous studies, our present findings demonstrate that CHN1 may be an important causative gene for different ethnicities with DRS.
Topics: Adolescent; Adult; Asian People; Child; Chimerin 1; Duane Retraction Syndrome; Family; Female; Humans; Male; Middle Aged; Mutation, Missense; Pedigree; Young Adult
PubMed: 33004823
DOI: 10.1038/s41598-020-73190-1