scholarly journals New locus underlying auriculocondylar syndrome (ARCND): 430 kb duplication involving TWIST1 regulatory elements

2021 ◽  
pp. jmedgenet-2021-107825
Author(s):  
Vanessa Luiza Romanelli Tavares ◽  
Sofia Ligia Guimarães-Ramos ◽  
Yan Zhou ◽  
Cibele Masotti ◽  
Suzana Ezquina ◽  
...  
Keyword(s):  
Linkage Analysis ◽  
Neural Crest ◽  
Tandem Duplication ◽  
Neural Crest Cells ◽  
Regulatory Elements ◽  
Lod Score ◽  
Pharyngeal Arches ◽  
Pathogenic Variants ◽  
The Family ◽  
Induced Pluripotent

BackgroundAuriculocondylar syndrome (ARCND) is a rare genetic disease that affects structures derived from the first and second pharyngeal arches, mainly resulting in micrognathia and auricular malformations. To date, pathogenic variants have been identified in three genes involved in the EDN1-DLX5/6 pathway (PLCB4, GNAI3 and EDN1) and some cases remain unsolved. Here we studied a large unsolved four-generation family.MethodsWe performed linkage analysis, resequencing and Capture-C to investigate the causative variant of this family. To test the pathogenicity of the CNV found, we modelled the disease in patient craniofacial progenitor cells, including induced pluripotent cell (iPSC)-derived neural crest and mesenchymal cells.ResultsThis study highlights a fourth locus causative of ARCND, represented by a tandem duplication of 430 kb in a candidate region on chromosome 7 defined by linkage analysis. This duplication segregates with the disease in the family (LOD score=2.88) and includes HDAC9, which is located over 200 kb telomeric to the top candidate gene TWIST1. Notably, Capture-C analysis revealed multiple cis interactions between the TWIST1 promoter and possible regulatory elements within the duplicated region. Modelling of the disease revealed an increased expression of HDAC9 and its neighbouring gene, TWIST1, in neural crest cells. We also identified decreased migration of iPSC-derived neural crest cells together with dysregulation of osteogenic differentiation in iPSC-affected mesenchymal stem cells.ConclusionOur findings support the hypothesis that the 430 kb duplication is causative of the ARCND phenotype in this family and that deregulation of TWIST1 expression during craniofacial development can contribute to the phenotype.

scholarly journals Stage-Dependent Differential Gene Expression Profiles of Cranial Neural Crest Cells Derived from Mouse Induced Pluripotent Stem Cells

2018 ◽  
Author(s):  
Ayano Odashima ◽  
Shoko Onodera ◽  
Akiko Saito ◽  
Takashi Nakamura ◽  
Yuuki Ogihara ◽  
...  
Keyword(s):  
Gene Expression ◽  
Neural Crest ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Neural Crest Cells ◽  
Cranial Neural Crest ◽  
Pharyngeal Arches ◽  
A Disintegrin And Metalloproteinase ◽  
Induced Pluripotent ◽  
Cranial Neural Crest Cells

AbstractCranial neural crest cells (cNCCs) comprise a multipotent population of cells that migrate into the pharyngeal arches of the vertebrate embryo and differentiate into a broad range of derivatives of the craniofacial organs. Consequently, migrating cNCCs are considered as one of the most attractive candidate sources of cells for regenerative medicine. In this study, we analyzed the gene expression profiles of cNCCs at different time points after induction by conducting three independent RNA sequencing experiments. We successfully induced cNCC formation from mouse induced pluripotent stem (miPS) cells by culturing them in neural crest inducing media for 14 days. We found that these cNCCs expressed several neural crest specifier genes but were lacking some previously reported specifiers, such as paired box 3 (Pax3), msh homeobox 1 (Msx1), and Forkhead box D3 (FoxD3), which are presumed to be essential for neural crest development in the embryo. Thus, a distinct molecular network may the control gene expression in miPS-derived cNCCs. We also found that c-Myc, ETS proto-oncogene 1, transcription factor (Ets1), and sex determining region Y-box 10 (Sox10) were only detected at 14 days after induction. Therefore, we assume that these genes would be useful markers for migratory cNCCs induced from miPS cells. Eventually, these cNCCs comprised a broad spectrum of protocadherin (Pcdh) and a disintegrin and metalloproteinase with thrombospondin motifs (Adamts) family proteins, which may be crucial in their migration.

Jaw and branchial arch mutants in zebrafish I: branchial arches

Development ◽  
1996 ◽  
Vol 123 (1) ◽  
pp. 329-344 ◽  
Author(s):  
T.F. Schilling ◽  
T. Piotrowski ◽  
H. Grandel ◽  
M. Brand ◽  
C.P. Heisenberg ◽  
...  
Keyword(s):  
Neural Crest ◽  
Zebrafish Embryo ◽  
Neural Crest Cells ◽  
Branchial Arch ◽  
Pigment Cells ◽  
Pharyngeal Arches ◽  
Pectoral Fins ◽  
Branchial Arches ◽  
Group Members ◽  
The Brain

Jaws and branchial arches together are a basic, segmented feature of the vertebrate head. Seven arches develop in the zebrafish embryo (Danio rerio), derived largely from neural crest cells that form the cartilaginous skeleton. In this and the following paper we describe the phenotypes of 109 arch mutants, focusing here on three classes that affect the posterior pharyngeal arches, including the hyoid and five gill-bearing arches. In lockjaw, the hyoid arch is strongly reduced and subsets of branchial arches do not develop. Mutants of a large second class, designated the flathead group, lack several adjacent branchial arches and their associated cartilages. Five alleles at the flathead locus all lead to larvae that lack arches 4–6. Among 34 other flathead group members complementation tests are incomplete, but at least six unique phenotypes can be distinguished. These all delete continuous stretches of adjacent branchial arches and unpaired cartilages in the ventral midline. Many show cell death in the midbrain, from which some neural crest precursors of the arches originate. lockjaw and a few mutants in the flathead group, including pistachio, affect both jaw cartilage and pigmentation, reflecting essential functions of these genes in at least two neural crest lineages. Mutants of a third class, including boxer, dackel and pincher, affect pectoral fins and axonal trajectories in the brain, as well as the arches. Their skeletal phenotypes suggest that they disrupt cartilage morphogenesis in all arches. Our results suggest that there are sets of genes that: (1) specify neural crest cells in groups of adjacent head segments, and (2) function in common genetic pathways in a variety of tissues including the brain, pectoral fins and pigment cells as well as pharyngeal arches.

sucker encodes a zebrafish Endothelin-1 required for ventral pharyngeal arch development

Development ◽  
2000 ◽  
Vol 127 (17) ◽  
pp. 3815-3828 ◽  
Author(s):  
C.T. Miller ◽  
T.F. Schilling ◽  
K. Lee ◽  
J. Parker ◽  
C.B. Kimmel
Keyword(s):  
Neural Crest ◽  
Expression Patterns ◽  
Neural Crest Cells ◽  
Paraxial Mesoderm ◽  
Dorsoventral Patterning ◽  
Surface Ectoderm ◽  
Pharyngeal Arches ◽  
Endothelin 1 ◽  
Lower Jaw ◽  
Arch Neural

Mutation of sucker (suc) disrupts development of the lower jaw and other ventral cartilages in pharyngeal segments of the zebrafish head. Our sequencing, cosegregation and rescue results indicate that suc encodes an Endothelin-1 (Et-1). Like mouse and chick Et-1, suc/et-1 is expressed in a central core of arch paraxial mesoderm and in arch epithelia, both surface ectoderm and pharyngeal endoderm, but not in skeletogenic neural crest. Long before chondrogenesis, suc/et-1 mutant embryos have severe defects in ventral arch neural crest expression of dHAND, dlx2, msxE, gsc, dlx3 and EphA3 in the anterior arches. Dorsal expression patterns are unaffected. Later in development, suc/et-1 mutant embryos display defects in mesodermal and endodermal tissues of the pharynx. Ventral premyogenic condensations fail to express myoD, which correlates with a ventral muscle defect. Further, expression of shh in endoderm of the first pharyngeal pouch fails to extend as far laterally as in wild types. We use mosaic analyses to show that suc/et-1 functions nonautonomously in neural crest cells, and is thus required in the environment of postmigratory neural crest cells to specify ventral arch fates. Our mosaic analyses further show that suc/et-1 nonautonomously functions in mesendoderm for ventral arch muscle formation. Collectively our results support a model for dorsoventral patterning of the gnathostome pharyngeal arches in which Et-1 in the environment of the postmigratory cranial neural crest specifies the lower jaw and other ventral arch fates.

scholarly journals Immunological Properties of Neural Crest Cells Derived from Human Induced Pluripotent Stem Cells

2019 ◽  
Vol 28 (1) ◽  
pp. 28-43 ◽  
Author(s):  
Shota Fujii ◽  
Satoru Yoshida ◽  
Emi Inagaki ◽  
Shin Hatou ◽  
Kazuo Tsubota ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Crest ◽  
Induced Pluripotent Stem Cells ◽  
Pluripotent Stem Cells ◽  
Neural Crest Cells ◽  
Immunological Properties ◽  
Induced Pluripotent

High Levels of Protein C Are Determinated by PROCR H3 in a Dutch Family.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2139-2139
Author(s):  
Maria Carolina Pintao ◽  
Sara Roshani ◽  
Marieke C.H. de Visser ◽  
Cris Tieken ◽  
Michael W.T. Tanck ◽  
...  
Keyword(s):  
Linkage Analysis ◽  
Candidate Genes ◽  
Protein C ◽  
Transmembrane Domain ◽  
Family Members ◽  
Endothelial Protein C Receptor ◽  
Lod Score ◽  
Chromosome 20 ◽  
The Family ◽  
The Mean

Abstract Abstract 2139 Poster Board II-116 The natural anticoagulant protein C (PC) circulates in blood at a concentration of about 60 nM. Inter-individual variations in the levels of PC are in part genetically determined, but which loci in the genome are involved is only partially known. In a recent study we identified a locus on chromosome 20 which was associated with high PC levels in a large pedigree from the GENES study (LOD score >5 at 55 cMorgan). Candidate genes related to the PC pathway under the LOD-1 region encoded FOXA2 (previously known as HNF3 beta, a nuclear factor regulating protein C gene transcription), thrombomodulin (THBD,which is key to activation of PC), and the endothelial protein C receptor (PROCR). Here we present data that pinpoint a SNP in PROCRas being responsible for the observed segregation of high PC levels. The pedigree has 218 members and was ascertained through a proband with a family history of venous thrombosis (VT). Classical genetic risk factors for thrombosis (i.e. PC-, PS-, antithrombin deficiency, factor V Leiden and prothrombin G20201A) were not present. Complete medical data, plasma measurements and DNA was available for 161 family members. The mean age was 47±15 (range 15-87) years. The mean PC plasma level was 116±25% (range 72-212). Four family members had experienced VT and 2 had had recurrence. These symptomatic members had normal to high PC levels (66, 82, 114 and 178%).Haplotypes (and genotypes) for PROCR were determined in the family members by TaqMan assay using tag SNPs (single nucleotide polymorphisms) and PROCR H3 was associated with the levels of PC in the family. Furthermore, the promoter, exons, and 3`UTR of the 3 candidate genes were sequenced in 13 individuals, 9 with high and 4 with normal plasma PC levels. Critical SNPs that were encountered during sequencing were genotyped in all family members, namely FOXA2 rs1055080 (3`UTR) and rs2277764 (promoter region). As those 2 SNPs were inherited together in the set of 13 patients and also in the LETS (data not shown), our further analysis used only rs1055080. Plasma soluble endothelial protein C receptor (sEPCR) and soluble thrombomodulin (sTM) levels were measured with an ELISA assay. PC and sEPCR and levels were compared between PROCR H3 and FOXA2 rs1055080 carriers and non carriers by Student's t-test. sTM was analyzed by Mann-Whitney test. Association between PC levels and sEPCR/sTM levels were evaluated using linear regression analysis. Afterwards associations were adjusted for the PROCR H3 and FOXA2 rs1055080 SNP separately to detect their possible confounding effect. DNA sequencing only yielded previously reported SNPs in FOXA2, THBD and PROCR. Only the above mentioned SNPs were associated with PC plasma levels. Linkage analysis for PC levels using the original markers (from Marshifield) and adding the new PROCR and FOXA2 SNPs did not change the LOD score. When the analysis was adjusted for the mentioned markers, the LOD score dropped below 2. sEPCR has a bimodal distribution; mean ± SD was 103±27 ng/ml for the first mode and 262±70 ng/ml for the second mode. Median (range) sTM was 1.2 ng/ml (0.1-4). Linkage analysis for sEPCR levels yielded a high LOD score (above 6) that was accentuated to above 8 when PROCR H3 was included as a marker. For sTM, the LOD score was low with every combination of markers. PC, sEPCR and sTM levels were compared between PROCR H3 carriers and non-carriers and both PC levels and sEPCR levels were influenced by this PROCR haplotype, but not sTM. In conclusion, chromosome 20 harbors a locus which influences PC levels and also the levels of sEPCR, but not the levels of sTM. A detailed analysis with SNPs in PROCR, THBD and FOXA2suggests that the so-called PROCR H3 is directly responsible for the increased PC and sEPCR levels in this family. PROCR H3 is known to represent a g.A6936G substitution leading to a p.Ser219Gly replacement in the transmembrane domain of EPCR. The Gly219 isoform is more sensitive to sheddases (such as the ADAM17 metalloprotease) and is associated with generation of truncated mRNA lacking the transmembrane domain. However, the exact mechanism by which EPCR and sEPCR levels influence the level of PC remains to be determined Disclosures: No relevant conflicts of interest to declare.

scholarly journals PDS Is a New Susceptibility Gene to Autoimmune Thyroid Diseases: Association and Linkage Study

2003 ◽  
Vol 88 (5) ◽  
pp. 2274-2280 ◽  
Author(s):  
Hassen Hadj Kacem ◽  
Ahmed Rebai ◽  
Noureddine Kaffel ◽  
Saber Masmoudi ◽  
Mohamed Abid ◽  
...  
Keyword(s):  
Linkage Analysis ◽  
Transmembrane Protein ◽  
Susceptibility Gene ◽  
Association Test ◽  
Lod Score ◽  
Autoimmune Thyroid ◽  
The Family ◽  
Family Based ◽  
Idiopathic Myxedema ◽  
Pds Gene

Autoimmune thyroid disease (AITD), including Graves’ disease (GD), Hashimoto thyroiditis (HT), and primary idiopathic myxedema, is caused by multiple genetic and environmental factors. Genes involved in immune response and/or thyroid physiology appear to influence susceptibility to disease. The PDS gene (7q31), responsible for Pendred syndrome (congenital sensorineural hearing loss and goiter), encodes a transmembrane protein known as pendrin. Pendrin is an apical porter of iodide in the thyroid. To evaluate the contribution of PDS gene in the genetic susceptibility of AITD, we examined four microsatellite markers in the gene region. Two hundred thirty-three unrelated patients (GD,141; HT, 54; primary idiopathic myxedema, 38), 15 multiplex AITD families (104 individuals/46 patients) and 154 normal controls were genotyped. Analysis of case-control data showed a significant association of D7S496 and D7S2459 with GD (P = 10−3) and HT (P = 1.07 10−24), respectively. The family-based association test showed significant association and linkage between AITDs and alleles 121 bp of D7S496 and 173 bp of D7S501. Results obtained by transmission disequilibrium test are in good agreement with those obtained by the family-based association test. Indeed, evidence for linkage and association of allele 121 bp of D7S496 with AITD was confirmed (P = 0.0114). Multipoint nonparametric linkage analysis using MERLIN showed intriguing evidence for linkage with marker D7S496 in families with only GD patients [Z = 2.12, LOD = 0.81, P = 0.026]. Single-point and multipoint parametric LOD score linkage analysis was also performed. Again, the highest multipoint parametric LOD score was found for marker D7S496 (LOD = 1.23; P = 0.0086) in families segregating for GD under a dominant model. This work suggests that the PDS gene should be considered a new susceptibility gene to AITDs with varying contributions in each pathology.

The chinless mutation and neural crest cell interactions in zebrafish jaw development

Development ◽  
1996 ◽  
Vol 122 (5) ◽  
pp. 1417-1426 ◽  
Author(s):  
T.F. Schilling ◽  
C. Walker ◽  
C.B. Kimmel
Keyword(s):  
Neural Crest ◽  
Neural Crest Cell ◽  
Neural Crest Cells ◽  
Paraxial Mesoderm ◽  
Wild Type ◽  
Host Genotype ◽  
Pharyngeal Arches ◽  
Expression Studies ◽  
Gene Expression Studies ◽  
Cranial Neural Crest Cells

During vertebrate development, neural crest cells are thought to pattern many aspects of head organization, including the segmented skeleton and musculature of the jaw and gills. Here we describe mutations at the gene chinless, chn, that disrupt the skeletal fates of neural crest cells in the head of the zebrafish and their interactions with muscle precursors. chn mutants lack neural-crest-derived cartilage and mesoderm-derived muscles in all seven pharyngeal arches. Fate mapping and gene expression studies demonstrate the presence of both undifferentiated cartilage and muscle precursors in mutants. However, chn blocks differentiation directly in neural crest, and not in mesoderm, as revealed by mosaic analyses. Neural crest cells taken from wild-type donor embryos can form cartilage when transplanted into chn mutant hosts and rescue some of the patterning defects of mutant pharyngeal arches. In these cases, cartilage only forms if neural crest is transplanted at least one hour before its migration, suggesting that interactions occur transiently in early jaw precursors. In contrast, transplanted cells in paraxial mesoderm behave according to the host genotype; mutant cells form jaw muscles in a wild-type environment. These results suggest that chn is required for the development of pharyngeal cartilages from cranial neural crest cells and subsequent crest signals that pattern mesodermally derived myocytes.

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