Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
???displayArticle.abstract???
Nager syndrome is a rare human developmental disorder characterized by hypoplastic neural crest-derived craniofacial bones and limb defects. Mutations in SF3B4 gene, which encodes a component of the spliceosome, are a major cause for Nager. A review of the literature indicates that 45% of confirmed cases are also affected by conductive, sensorineural or mixed hearing loss. Conductive hearing loss is due to defective middle ear ossicles, which are neural crest derived, while sensorineural hearing loss typically results from defective inner ear or vestibulocochlear nerve, which are both derived from the otic placode. Animal model of Nager syndrome indicates that upon Sf3b4 knockdown cranial neural crest progenitors are depleted, which may account for the conductive hearing loss in these patients. To determine whether Sf3b4 plays a role in otic placode formation we analyzed the impact of Sf3b4 knockdown on otic development. Sf3b4-depleted Xenopus embryos exhibited reduced expression of several pan-placodal genes six1, dmrta1 and foxi4.1. We confirmed the dependence of placode genes expression on Sf3b4 function in animal cap explants expressing noggin, a BMP antagonist critical to induce placode fate in the ectoderm. Later in development, Sf3b4 morphant embryos had reduced expression of pax8, tbx2, otx2, bmp4 and wnt3a at the otic vesicle stage, and altered otic vesicle development. We propose that in addition to the neural crest, Sf3b4 is required for otic development, which may account for sensorineural hearing loss in Nager syndrome.
Fig. 1. Sf3b4 knockdown affects six1 and dmrta1 expression at the neurula stage. (a) Unilateral injection of increasing doses of Sf3b4MO (2 ng–20 ng) interfere with six1 and dmrta1 expression. RNA encoding the lineage tracer β-galactosidase was co-injected with Sf3b4MO to identify the injected side (red staining, right side in all panels). The arrows point to the affected placode areas. Anterior views, dorsal to top. (b) Quantification of six1 and dmrta1 ISH results. The numbers on the top of each bar indicate the number of embryos analyzed from three independent experiments.
Fig. 2. Sf3b4 knockdown affects a broad range of placode genes. (a) Unilateral injection of Sf3b4MO (10 ng) interfere with six1, dmrta1, foxi4.1 and pax8 expression. RNA encoding the lineage tracer β-galactosidase was co-injected with Sf3b4MO to identify the injected side (red staining, right side in all panels). The arrows point to the affected placode areas. pax8 is also expressed posteriorly in the prospective pronephros (asterisks). Anterior views, dorsal to top. (b) Quantification of the ISH results. The numbers on the top of each bar indicate the number of embryos analyzed from at least three independent experiments. Injection of a CoMO at the same concentration (10 ng) had no impact of the expression of these genes. ∗∗∗p<0.0001, Chi-squared test.
Fig. 3. Placode genes induction by noggin require Sf3b4. (a) Animal cap explants dissected from blastula stage embryos (NF stage 9) injected at the 2-cell stage with noggin mRNAs alone or in combination with Sf3b4MO were cultured for 8 h. (b) qRT-PCR analyses indicate that Sf3b4MO blocks placode (six1 and eya1) and neural plate (sox2) gene induction by Noggin in animal cap explants, and restores epidermal fate (krt12.4). Values are normalized to odc and presented as mean ± s.e.m.; (∗) p < 0.05 and (∗∗) p < 0.001 (Student’s t-test), from three independent samples.
Fig. 4. Sf3b4 knockdown affects otic vesicle gene expression. (a) Schematic representation of the expression pattern of pax8, tbx2, wnt3a, bmp4, and otx2 in the epithelium of the otic vesicle of NF stage 35 embryos. A, anterior; P posterior; D, dorsal; V, ventral. (b) In embryos injected with 10 ng of Sf3b4MO the regional otic expression of pax8, tbx2, wnt3a, bmp4, and otx2 is disrupted. RNA encoding the lineage tracer β-galactosidase was co-injected with Sf3b4MO to identify the injected side (red staining). The black arrows point to the otic expression of each gene on the control side and the white arrows to the corresponding affected areas on the Sf3b4MO-injected side. For orientation, the position of the eye is indicated (asterisks). Lateral views, anterior to left, dorsal to top. (c) Quantification of the ISH results. The numbers on the top of each bar indicate the number of embryos analyzed from three independent experiments.
Fig. 5. Sf3b4 knockdown affects otic vesicle development. (a) Serial sections (#1-anterior to #14-posterior) through a representative tbx2-stained embryo (NF stage 35) injected with 10 ng of Sf3b4MO. On the injected side (left side; double arrows), the size of the otic vesicle is reduced as compared to the control side (right side; single arrows). (b) The size of the otic vesicle (μm) was determined based on the number of sections (12 μm) required to cut the entire otic vesicle on control vs. injected sides. On average this represents 11.33 sections or 136 μm (control) vs. 6.77 sections or 81.33 μm (Sf3b4MO-injected). ∗p < 0.05 (Unpaired t-test with Welch’s correction), n=9.
Fig. 6. Sf3b4 knockdown affects olfactory gene expression. (a) Unilateral injection of Sf3b4MO (10 ng) interferes with dmrta1, ebf2 and six1 expression. RNA encoding the lineage tracer β-galactosidase was co-injected with Sf3b4MO to identify the injected side (red staining, right side in all panels). The arrows point to reduce gene expression in the olfactory epithelium. (b) Quantification of the ISH results. The numbers on the top of each bar indicate the number of embryos analyzed from two independent experiments. Injection of a CoMO at the same concentration (10 ng) had no impact of the expression of these genes. ∗∗∗p<0.0001, Chi-squared test.
Abdollahi Fakhim,
A case report: nager acrofacial dysostosis.
2012, Pubmed
Abdollahi Fakhim,
A case report: nager acrofacial dysostosis.
2012,
Pubmed
Aylsworth,
Nager acrofacial dysostosis: male-to-male transmission in 2 families.
1991,
Pubmed
Battaglia,
Nager acrofacial dysostosis with autosomal dominant inheritance: implications for the otolaryngologist.
2000,
Pubmed
Beauchamp,
Spliceosomopathies and neurocristopathies: Two sides of the same coin?
2020,
Pubmed
Bellanger,
[Nager syndrome associated with tetralogy of Fallot: A frequent association?].
2015,
Pubmed
Bernier,
Haploinsufficiency of SF3B4, a component of the pre-mRNA spliceosomal complex, causes Nager syndrome.
2012,
Pubmed
Bozatlıoğlu,
Dental Management of a Patient with Nager Acrofacial Dysostosis.
2015,
Pubmed
Brugmann,
Six1 promotes a placodal fate within the lateral neurogenic ectoderm by functioning as both a transcriptional activator and repressor.
2004,
Pubmed
,
Xenbase
Bukowska-Olech,
Targeted Next-Generation Sequencing in the Diagnosis of Facial Dysostoses.
2020,
Pubmed
Burns,
Xath5 regulates neurogenesis in the Xenopus olfactory placode.
2002,
Pubmed
,
Xenbase
Cassina,
A synonymous splicing mutation in the SF3B4 gene segregates in a family with highly variable Nager syndrome.
2017,
Pubmed
Castori,
A 22-Week-Old Fetus with Nager Syndrome and Congenital Diaphragmatic Hernia due to a Novel SF3B4 Mutation.
2014,
Pubmed
Chemke,
Autosomal recessive inheritance of Nager acrofacial dysostosis.
1988,
Pubmed
Czeschik,
Clinical and mutation data in 12 patients with the clinical diagnosis of Nager syndrome.
2013,
Pubmed
Danziger,
Nager's acrofacial dysostosis. Case report and review of the literature.
1990,
Pubmed
Davies,
The first reported treatment of Nager syndrome associated hearing loss with bone-anchored hearing aids: case report.
2012,
Pubmed
Denu,
Synchronous Bilateral Breast Cancer in a Patient With Nager Syndrome.
2017,
Pubmed
Devotta,
Sf3b4-depleted Xenopus embryos: A model to study the pathogenesis of craniofacial defects in Nager syndrome.
2016,
Pubmed
,
Xenbase
Dimitrov,
Acrofacial dysostosis type Rodríguez.
2005,
Pubmed
Dixon,
Tcof1/Treacle is required for neural crest cell formation and proliferation deficiencies that cause craniofacial abnormalities.
2006,
Pubmed
Drivas,
The final demise of Rodriguez lethal acrofacial dysostosis: A case report and review of the literature.
2019,
Pubmed
Drozniewska,
Second-trimester prenatal diagnosis of Nager syndrome with a deletion including SF3B4 detected by chromosomal microarray.
2020,
Pubmed
Freyer,
Dual embryonic origin of the mammalian otic vesicle forming the inner ear.
2011,
Pubmed
Goldstein,
Nager acrofacial dysostosis: evidence for apparent heterogeneity.
1988,
Pubmed
Gordon,
EFTUD2 haploinsufficiency leads to syndromic oesophageal atresia.
2012,
Pubmed
Griffin,
Spliceosomopathies: Diseases and mechanisms.
2020,
Pubmed
Groeper,
Anaesthetic implications of Nager syndrome.
2002,
Pubmed
Harland,
In situ hybridization: an improved whole-mount method for Xenopus embryos.
1991,
Pubmed
,
Xenbase
Hayata,
A Case of Nager Syndrome Diagnosed Before Birth.
2019,
Pubmed
Hayata,
Expression of Xenopus T-box transcription factor, tbx2 in Xenopus embryo.
1999,
Pubmed
,
Xenbase
Hecht,
The Nager syndrome.
1987,
Pubmed
Heller,
Xenopus Pax-2/5/8 orthologues: novel insights into Pax gene evolution and identification of Pax-8 as the earliest marker for otic and pronephric cell lineages.
1999,
Pubmed
,
Xenbase
Herrmann,
Otologic and audiologic features of Nager acrofacial dysostosis.
2005,
Pubmed
Hong,
The activity of Pax3 and Zic1 regulates three distinct cell fates at the neural plate border.
2007,
Pubmed
,
Xenbase
Huang,
The doublesex-related gene, XDmrt4, is required for neurogenesis in the olfactory system.
2005,
Pubmed
,
Xenbase
Irving,
Rodriguez acrofacial dysostosis is caused by apparently de novo heterozygous mutations in the SF3B4 gene.
2016,
Pubmed
Jones,
Prevention of the neurocristopathy Treacher Collins syndrome through inhibition of p53 function.
2008,
Pubmed
Jones,
DVR-4 (bone morphogenetic protein-4) as a posterior-ventralizing factor in Xenopus mesoderm induction.
1992,
Pubmed
,
Xenbase
Jourdain,
Multiplex targeted high-throughput sequencing in a series of 352 patients with congenital limb malformations.
2020,
Pubmed
Kavadia,
Nager syndrome (preaxial acrofacial dysostosis): a case report.
2004,
Pubmed
Kawira,
Acrofacial dysostosis with severe facial clefting and limb reduction.
1984,
Pubmed
Kumar,
Nager acrofacial dysostosis: a rare genetic disorder causing bilateral temperomandibular joint ankylosis in a 10-year-old girl.
2015,
Pubmed
Lehalle,
A review of craniofacial disorders caused by spliceosomal defects.
2015,
Pubmed
Likar,
Diagnostic outcomes of exome sequencing in patients with syndromic or non-syndromic hearing loss.
2018,
Pubmed
Lin,
Nager syndrome: a case report.
2012,
Pubmed
Lines,
Haploinsufficiency of a spliceosomal GTPase encoded by EFTUD2 causes mandibulofacial dysostosis with microcephaly.
2012,
Pubmed
Lund,
Prenatal diagnosis of Nager syndrome in a 12-week-old fetus with a whole gene deletion of SF3B4 by chromosomal microarray.
2016,
Pubmed
Lynch,
Disrupted auto-regulation of the spliceosomal gene SNRPB causes cerebro-costo-mandibular syndrome.
2014,
Pubmed
Malik,
Limbal dermoid in Nager acrofacial dysostosis: a rare case report.
2014,
Pubmed
Marques,
Altered mRNA Splicing, Chondrocyte Gene Expression and Abnormal Skeletal Development due to SF3B4 Mutations in Rodriguez Acrofacial Dysostosis.
2016,
Pubmed
McPherson,
Rodriguez syndrome with SF3B4 mutation: a severe form of Nager syndrome?
2014,
Pubmed
Minoux,
Molecular mechanisms of cranial neural crest cell migration and patterning in craniofacial development.
2010,
Pubmed
Mishra,
A.B.R. in Nager type acrofacial dysostosis syndrome.
1999,
Pubmed
Miyawaki,
Rodriguez lethal acrofacial dysostosis syndrome with pulmonary hypoplasia.
2009,
Pubmed
Nur,
Possible autosomal recessive inheritance in an infant with acrofacial dysostosis similar to Nager syndrome.
2013,
Pubmed
Paladini,
Prenatal ultrasound diagnosis of Nager syndrome.
2003,
Pubmed
Pandur,
Xenopus Six1 gene is expressed in neurogenic cranial placodes and maintained in the differentiating lateral lines.
2000,
Pubmed
,
Xenbase
Pannese,
The Xenopus homologue of Otx2 is a maternal homeobox gene that demarcates and specifies anterior body regions.
1995,
Pubmed
,
Xenbase
Passos-Bueno,
Syndromes of the first and second pharyngeal arches: A review.
2009,
Pubmed
Petit,
Nager syndrome: confirmation of SF3B4 haploinsufficiency as the major cause.
2014,
Pubmed
Pohl,
Sequence and expression of FoxB2 (XFD-5) and FoxI1c (XFD-10) in Xenopus embryogenesis.
2002,
Pubmed
,
Xenbase
Ritter,
Neural crest contributions to the ear: Implications for congenital hearing disorders.
2019,
Pubmed
Rodríguez,
New acrofacial dysostosis syndrome in 3 sibs.
1990,
Pubmed
Rosa,
Nager syndrome and Pierre Robin sequence.
2015,
Pubmed
Saint-Germain,
Specification of the otic placode depends on Sox9 function in Xenopus.
2004,
Pubmed
,
Xenbase
Saint-Jeannet,
Whole-Mount In Situ Hybridization of Xenopus Embryos.
2017,
Pubmed
,
Xenbase
Schlosser,
Molecular anatomy of placode development in Xenopus laevis.
2004,
Pubmed
,
Xenbase
Sermer,
Acrofacial dysostosis syndrome type Rodriguez: prenatal diagnosis and autopsy findings.
2007,
Pubmed
Slack,
An interaction between dorsal and ventral regions of the marginal zone in early amphibian embryos.
1980,
Pubmed
,
Xenbase
Streit,
Origin of the vertebrate inner ear: evolution and induction of the otic placode.
2001,
Pubmed
Tay,
A Case Report of Absent Epiglottis in Children With Nager Syndrome: Its Impact on Swallowing.
2017,
Pubmed
Trainor,
Facial dysostoses: Etiology, pathogenesis and management.
2013,
Pubmed
Ural,
Rodriguez lethal acrofacial dysostosis syndrome with ambiguous genitalia.
2016,
Pubmed
Waggoner,
Deletion of 1q in a patient with acrofacial dysostosis.
1999,
Pubmed
Wessels,
Prenatal diagnosis and confirmation of the acrofacial dysostosis syndrome type Rodriguez.
2002,
Pubmed
Whitfield,
Development of the inner ear.
2015,
Pubmed
Wieczorek,
Human facial dysostoses.
2013,
Pubmed
Wieczorek,
Compound heterozygosity of low-frequency promoter deletions and rare loss-of-function mutations in TXNL4A causes Burn-McKeown syndrome.
2014,
Pubmed
Will,
Spliceosome structure and function.
2011,
Pubmed
Wolda,
Overlapping expression of Xwnt-3A and Xwnt-1 in neural tissue of Xenopus laevis embryos.
1993,
Pubmed
,
Xenbase
Wu,
Ankylosis of temporomandibular joints after mandibular distraction osteogenesis in patients with Nager syndrome: Report of two cases and literature review.
2017,
Pubmed
Yamada,
Heterozygous mutation of the splicing factor Sf3b4 affects development of the axial skeleton and forebrain in mouse.
2020,
Pubmed
Zhao,
Broad-spectrum next-generation sequencing-based diagnosis of a case of Nager syndrome.
2020,
Pubmed
Zori,
Preaxial acrofacial dysostosis (Nager syndrome) associated with an inherited and apparently balanced X;9 translocation: prenatal and postnatal late replication studies.
1993,
Pubmed