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PubMed2026

Genomic basis of developmental defects of enamel and sex-specific effects.

We conducted a multi-ancestry genome-wide association study (GWAS) of developmental defects of enamel (DDE) in the primary dentition among 6,061 U.S. preschool-aged children (3-5 years). We investigated four DDE phenotypes (demarcated opacities, diffuse opacities, hypoplastic defects, and a combined DDE trait) leveraging main-effect models, joint gene-sex interaction testing (2df), and sex-stratified analyses. SNP-based heritability for the combined DDE trait was estimated at 20%, with concordance analyses robustly supporting a genetic etiology. We identified 39 unique genome-wide significant loci (P<5&#xd7;10 ), with five surpassing a study-wide Bonferroni-corrected statistical significance criterion (P<1.25&#xd7;10 9), including Y RNA and ALDH1A1. The main-effect GWAS identified 20 loci, including HBS1L and MYB, genes regulating hematopoiesis with plausible roles in amelogenesis. Joint test and sex-stratified analyses revealed 19 additional loci, including ALDH1A1, TENM2, and DLGAP2, demonstrating sex-specific heterogeneity. Nineteen loci exhibited sex-specific differences after Bonferroni correction (P<2x10-3), including genes involved in retinoic acid signaling (ALDH1A1), odontogenesis (TENM2), and neurodevelopment (DLGAP2, CDH10). Pathway enrichment highlighted ectodermal and synapse organization networks, suggesting shared etiological mechanisms between DDE and systemic conditions like neurofibromatosis and autism spectrum disorder. Notably, no locus generalized in an external GWAS of permanent dentition DDE, underscoring fundamental biological differences in the genetic architectures governing primary versus permanent enamel formation. Crucially, a comprehensive cross-trait pleiotropy lookup against early childhood caries (ECC) revealed no shared genetic architecture, supporting the notion that the established clinical and epidemiological association between DDE and ECC is likely driven by structural defects increasing caries lesion susceptibility rather than genetic pleiotropy. By integrating gene-sex interaction testing, this study offers novel insights into the complex, sexually dimorphic genetic etiology of DDE and augments the biological evidence base that can support the development of precision pediatric dentistry.

developmental defects of enamel↗
PubMed2005

Autogenous calvarial bone graft harvest: intraoperational complications.

In the field of maxillofacial reconstructive surgery, the authors take into consideration the autogenous calvarial bone graft harvest technique for the correction of maxilla bone defects and examine some salient aspects such as technical problems and possible surgical complications.

Alveolar Ridge Augmentation↗
PubMed1985

EEC syndrome without ectrodactyly? Report of 8 cases.

Eight cases are presented from two families with a variable manifestation of the EEC syndrome. In the first family only one of three affected persons suffers from limb defects. In the second family all five affected have a different pattern of symptoms and only two of them show limb defects. The described families as well as at least one literature report confirm that ectrodactyly is not an obligate symptom of the EEC syndrome.

Abnormalities, Multiple↗
PubMed2001

Xenopus Dishevelled signaling regulates both neural and mesodermal convergent extension: parallel forces elongating the body axis.

During amphibian development, non-canonical Wnt signals regulate the polarity of intercalating dorsal mesoderm cells during convergent extension. Cells of the overlying posterior neural ectoderm engage in similar morphogenetic cell movements. Important differences have been discerned in the cell behaviors associated with neural and mesodermal cell intercalation, raising the possibility that different mechanisms may control intercalations in these two tissues. In this report, targeted expression of mutants of Xenopus Dishevelled (Xdsh) to neural or mesodermal tissues elicited different defects that were consistent with inhibition of either neural or mesodermal convergent extension. Expression of mutant Xdsh also inhibited elongation of neural tissues in vitro in Keller sandwich explants and in vivo in neural plate grafts. Targeted expression of other Wnt signaling antagonists also inhibited neural convergent extension in whole embryos. In situ hybridization indicated that these defects were not due to changes in cell fate. Examination of embryonic phenotypes after inhibition of convergent extension in different tissues reveals a primary role for mesodermal convergent extension in axial elongation, and a role for neural convergent extension as an equalizing force to produce a straight axis. This study demonstrates that non-canonical Wnt signaling is a common mechanism controlling convergent extension in two very different tissues in the Xenopus embryo and may reflect a general conservation of control mechanisms in vertebrate convergent extension.

Adaptor Proteins, Signal Transducing↗
PubMed1996

Aplasia cutis congenita. Case report.

The authors report the use of intraoperative tissue expansion in the treatment of a neonate with aplasia cutis congenita, a congenital defect of the scalp and skull. The case for immediate surgical intervention is presented, and intraoperative tissue expansion and cranioplasty are recommended as components of an effective surgical approach.

Adult↗
PubMed2004

Pax9 is required for filiform papilla development and suppresses skin-specific differentiation of the mammalian tongue epithelium.

The epidermis is a derivative of the surface ectoderm. It forms a protective barrier and specific appendages including hair, nails, and different eccrine glands. The surface ectoderm also forms the epithelium of the oral cavity and tongue, which develop a slightly different barrier and form different appendages such as teeth, filiform papillae, taste papillae, and salivary glands. How this region-specific differentiation is genetically controlled is largely unknown. We show here that Pax9, which is expressed in the epithelium of the tongue but not in skin, regulates several aspects of tongue-specific epithelial differentiation. In Pax9-deficient mice filiform papillae lack the anterior-posterior polarity, a defect that is associated with temporal-spatial changes in Hoxc13 expression. Barrier formation is disturbed in the mutant tongue and genome-wide expression profiling revealed that the expression of specific keratins (Krt), keratin-associated proteins, and members of the epidermal differentiation complex is significantly down-regulated. In situ hybridization demonstrated that several 'hard' keratins, Krt1-5, Krt1-24, and Krt2-16, are not expressed in the absence of Pax9. Notably, specific 'soft' keratins, Krt2-1 and Krt2-17, normally weakly expressed in the tongue but present at high levels in skin and in orthokeratinized oral dysplasia are up-regulated in the mutant tongue epithelium. This result indicates a partial trans-differentiation to an epithelium with skin-specific characteristics. Together, our findings show that Pax9 regulates appendage formation in the mammalian tongue and identify Pax9 as an important factor for the region-specific differentiation of the surface ectoderm.

Animals↗
PubMed1996

Regional differences in morphogenesis of the neuroepithelium suggest multiple mechanisms of spinal neurulation in the mouse.

A study of neuroepithelial morphogenesis in the mouse embryo has identified three modes of neural tube formation that occur consecutively as neurulation progresses along the spinal region. The three modes of neurulation differ in the extent to which the neuroepithelium exhibits formation of "hinge points', i.e. localised bending owing to reduction in apical surface area. In Mode 1, bending occurs only in the neuroepithelium overlying the notochord, creating a median hinge point. The neural folds remain straight along both apical and basal surfaces, resulting in a neural tube with a slitshaped lumen. In Mode 2, the neuroepithelium forms paired dorsolateral hinge points, as well as a median hinge point, whereas the remaining portions of the neuroepithelium do not bend. This produces a neural tube with a diamond-shaped lumen. In Mode 3 neurulation, the entire neuroepithelium exhibits bending, so that the cells specific hinge points are not discernible; the resulting neural tube has a circular lumen. The three modes of neurulation are present in all three strains of mice studied: C57BL/6, CBA/Ca and curly tail, a mutant predisposed to neural tube defects. However, curly tail embryos exhibit a delay in transition from Mode 2 to Mode 3, preceding faulty closure of the posterior neuropore. This heterogeneity of neurulation morphogenesis in the mouse embryo indicates that the underlying mechanisms may vary along the body axis. Specifically, we suggest that Mode 1 neurulation is driven largely by forces generated extrinsic to the neuroepithelium, in adjacent tissues, whereas Mode 3 neurulation is dependent primarily on forces generated intrinsic to the neuroepithelium. Down the body axis, there is a gradual decrease in the area of ectoderm involved in neural induction and, as neurulation reaches lower spinal levels, the newly induced neural plate exhibits marked indentation from the time of its first appearance. The transition from primary neurulation (neural folding of Mode 3 type) to secondary neurulation (neural tube formation by cavitation) appears to be a smooth continuation of this trend, with loss of contact between the newly induced neuroepithelium and the outside of the embryo.

Animals↗
PubMed2001

Mutational spectrum of the ED1 gene in X-linked hypohidrotic ectodermal dysplasia.

X-linked hypohidrotic ectodermal dysplasia (XLHED) is the most common form of the ectodermal dysplasias characterised by an abnormal development of eccrine sweat glands, hair and teeth. The ED1 gene responsible for the disorder undergoes extensive alternative splicing and to date few studies have concerned the full length transcript. We screened 52 unrelated families or sporadic cases for mutation in the full coding sequence of this gene. SSCA analysis or direct sequencing allowed identification of mutations in 34 families: one initiation defect, twenty-two missenses, two nonsense, eight insertions or deletions, and a large deletion encompassing all the ED1 gene. Fourteen of these mutations have not been previously described, including five missenses. One third of identified mutations were localised in codons 155 and 156, affecting CpG dinucleotides and nine of them correspond to the R156H missense. Hypothesis of a founder effect has been ruled out by haplotype analysis of flanking microsatellites. These recurrent mutations indicate the functional importance of the positively charged domain of the protein. Including our data, there are now 56 different mutations reported in 85 independent patients, that we have tabulated. Review of clinical features in the present series of affected males and female carriers showed no obvious correlation between the type of mutations, the phenotype and its severity. The X-chromosome pattern of inactivation in leucocytes showed little correlation with expressivity of the disease in female carriers. Finally this study is useful for functional studies of the protein and to define a diagnostic strategy for mutation screening of the ED1 gene.

Dosage Compensation, Genetic↗
PubMed2001

Expression and regulation of chicken fibroblast growth factor homologous factor (FHF)-4 during craniofacial morphogenesis.

Fibroblast growth factor homologous factors (FHFs) have been implicated in limb and nervous system development. In this paper we describe the expression of the cFHF-4 gene during chicken craniofacial development. cFHF-4 is expressed in the mesenchyme of the frontonasal process, and in the mesenchyme and ectoderm of the mandibular processes. The expression of cFHF-4 and other genes implicated in facial patterning have been analyzed in talpid(2) embryos or in the presence of exogenous retinoic acid. Talpid(2) mutants show abnormal patterns of gene expression, including up-regulation of cFHF-4 in the developing face, which correlate with defects in cartilage formation. By contrast, expression of cFHF-4 in the developing face is strongly downregulated by teratogenic doses of all-trans retinoic acid in a dose-dependent manner. Low levels of retinoic acid that produce distal upper beak truncations do not affect cShh, c-Patched-1, or c-Bmp-2 expression in the face, but downregulate cFHF-4 in the frontonasal process.

Animals↗
PubMed1998

Retinoic acid affects patterning along the anterior-posterior axis of the ascidian embryo.

Because retinoic acid (RA) is known to affect anterior posterior patterning in vertebrate embryos, it was questioned whether it shows similar effects in a more primitive chordate, the ascidian Halocynthia roretzi. Ascidian embryos treated with RA exhibited truncated phenotypes in a dose-dependent manner similar to the anterior truncations seen in vertebrate embryos. The most severely affected larvae possessed a round trunk without the papillae characteristic of the anterior terminal epidermis. Retinoic acid also altered the expression of HrHox-1 and Hroth in a dose-dependent manner. Expression of HrHox-1 increased, whereas expression of Hroth decreased with increasing levels of RA. In treated embryos, HrHox-1 was first expressed pan-ectodermally, then degraded in all but specific regions of the embryo. By contrast, initiation of Hroth expression was not affected, but epidermal expression was lost while expression in the neural tube narrowed toward the anterior in tail-bud embryos. These alterations in the expression of homeobox genes appear to correlate closely to the morphological defects elicited by RA treatment, suggesting broad conservation of developmental patterning mechanisms within the Phylum Chordata.

Animals↗
PubMed1985

Pathogenesis of the mouse forelimb deformity induced by acetazolamide: an electron microscopic study.

Scanning electron microscopic observations after removal of the epidermis from developing limb buds reveal a fine mesenchymal cell process meshwork (CPM). The relationship between apical ectodermal ridge (AER) development and CPM density was investigated and related to the postaxial reduction deformities induced by acetazolamide (AA). AA was given orally to pregnant mice at 9 A.M. and 4 P.M. of day 9 and 9 A.M. of day 10 (VP = 0) in a dose of 1,000 mg/kg. Forelimb ectrodactyly, especially on the right, was the most common deformity observed. Scanning electron microscopic observations showed that the AER in AA-treated right forelimb buds did not extend postaxially as far as that in controls. The postaxial region with the hypoplastic AER became defective. Scanning and transmission electron microscopic observations revealed that in control and treated right forelimb buds, the CPM underneath the typical AER was sparser than that underneath the dorsal or ventral non-ridge epidermis. However, in treated right forelimb buds, the CPM underneath a hypoplastic AER was denser than that underneath the normal AER. These findings suggest that AA-induced deformity results from a disturbance of the AER-mesenchymal interactions.

Abnormalities, Drug-Induced↗
PubMed1991

Aplasia cutis congenita associated with syndactyly and supernumerary nipples: report of a second family with similar clinical findings.

Aplasia cutis congenita (ACC) is a rare disorder characterized by localized absence of skin at birth. A subtype consisting of a solitary scalp defect in association with limb abnormalities has been described. We report a case of ACC in association with 3,4 syndactyly and supernumerary nipples with an apparent autosomal dominant inheritance pattern.

Abnormalities, Multiple↗
PubMed2000

[Aplasia cutis congenita in a newborn: etiopathogenic review and diagnostic approach].

Aplasia cutis congenita is a rare condition characterized by the congenital absence of epidermis, dermis and, in some cases, subcutaneous tissues. It was first described by Cordon in 1767 and more than 500 cases have been reported since, with an estimate incidence of 3 in 10,000 births. The lesions may occur on any body surface although localised agenesis of the scalp is the most frequent pattern. In approximately 20% of cases underlying bone defects are also found. Aplasia cutis congenita occurs as an isolated defect or with other associated anomalies. There is no unifying theory for the pathogenesis and large scalp defects present a management dilemma. We report a newborn with a large scalp defect in the midline at the vertex without associated malformations. There was no significant family history. Skull and extremities radiographs, chromosome analysis, cerebral and abdominal sonography were normal. Two methods of treatment were used: a conservative approach consisting of daily antiseptic dressing to allow scalp epithelialization improved conditions for secondary surgery at 30 days of life, closing the defect with local rotational flaps. The postoperative course was uneventful and an excellent cosmetic result was achieved.

Ectodermal Dysplasia↗
PubMed1990

Developmental expression of c-kit, a proto-oncogene encoded by the W locus.

Developmental expression of the c-kit proto-oncogene, a receptor tyrosine kinase encoded by the W locus, was investigated by in situ hybridization in normal mouse embryos. Early after implantation transcripts were detectable only in the maternal placenta (6 1/2-7 1/2 days p.c.). Subsequently (8 1/2 days p.c.) numerous ectodermal (neural tube, sensory placodes) and endodermal (embryonic gut) derivatives expressed c-kit. Later transcripts were detected also in the blood islands of the yolk sac and in the embryonic liver, the main sites of embryonic hemopoiesis. Around midgestation, transcripts accumulated in the branchial pouches and also in primordial germ cells of the genital ridges. This complex pattern of expression remained characteristic also later in gestation, when c-kit was expressed in highly differentiated structures of the craniofacial area, in presumptive melanoblasts and in the CNS. In the adult ovary, maternal c-kit transcripts were detected. They were present in the oocytes of both immature and mature ovarian follicles, but not in the male germ line, where c-kit expression may be down regulated. Thus, c-kit activity is complex and appears in multiple tissues including those that also display defects in mutations at the W locus where c-kit is encoded. Correlation between W phenotypes and c-kit expression, as well as the regulation of the complex and multiple expression of polypeptide growth factors and receptors, is discussed.

Alleles↗
PubMed2003

Disruption of eyelid and cornea development by targeted overexpression of the glucocorticoid receptor.

Glucocorticoid hormones act through the glucocorticoid receptor (GR) and they affect almost all physiological systems in the organism. We have previously reported that transgenic mice overexpressing GR under the control of the keratin k5 promoter (K5-GR mice) display severe phenotypic alterations in the epidermis and other ectoderm derivatives (Perez et al., 2001). In this work, we aimed to characterize the pathological consequences of GR targeted overexpression in the eyelid and cornea at late developmental stages. Despite glucocorticoids being widely prescribed as a topical treatment in ophthalmology, their potential role during ocular development in the embryo is not well understood. As shown by scanning electron microscopy analysis as well as by our histopathological and immunohistochemical data, long-term and newborn transgenic embryos showed unfused eyelids, along with proptosis of the globe and exposure of the anterior surface. In addition, epithelial defects were evident at the cornea. Our results indicate that GR overexpression affected the proliferation rate of targeted epithelia of the cornea and eyelid, thus demonstrating that GR was responsible for the arrest of epithelial proliferation of the developing eyelid edges, as well as for their destruction. We conclude that constitutive targeted overexpression of GR in the eyelid and corneal epithelium dramatically impairs ocular function in these transgenic mice.

Animals↗
PubMed1998

A simple molecular model of neurulation.

A molecular model for the morphogenesis of the central nervous system is built and solved by computer. The formalism rests on molecular-biological data gathered from insects and vertebrates during neural differentiation and neuronal fate specification. Two genetic, hierarchically organized switches are introduced, one associated with f1p4al tissue formation, and the other with neuronal specification. The model switches evolve in time, setting up very similar "prepatterns" of genetic activity in both insects and vertebrates, as observed experimentally. We introduce the hypothesis that cell adhesion and motion are regulated by the switches. If cell motion is turned on by the neural switch, the whole neural tissue (neural plate) thickens, buckles, and folds, ultimately creating a closed neural tube (primary neurulation). When mitoses are more frequent in neural plate tissue, ingression of a neural cell mass takes place instead (secondary neurulation). If cell motions are controlled by the neuronal switch, rather than by the neural one, the differentiation of isolated neuroblasts is observed, which delaminate individually (as in insect neural cord formation). The model thus displays the three major known patterns of neurogenesis; the transition between the vertebrate and insect cases is predicted to result from changes in genetic regulation downstream of the switch genes, and affecting cell adhesion and motility properties. Little is known experimentally about the concerned pathways: their importance as a fruitful area for future investigation is emphasized by our theoretical results.

Animals↗
PubMed2004

p63 gene analysis in Mexican patients with syndromic and non-syndromic ectrodactyly.

Ectrodactyly is a congenital limb malformation that involves a central reduction defect of the hands and/or feet which is frequently associated with other phenotypic abnormalities. The condition appears to be genetically heterogeneous and recently it has been demonstrated that mutations in the p63 gene, a homologue of the tumor suppressor gene p53, are the cause of at least four autosomal dominant genetic syndromes which feature ectrodactyly: ectrodactyly, ectodermal dysplasia, and facial clefting (EEC), split hand/split foot malformation (SHFM), limb-mammary syndrome (LMS), and acro-dermato-ungual-lacrimal-tooth syndrome (ADULT). In this study, genetic analysis of the p63 gene in a group of 13 patients with ectrodactyly (syndromic and isolated) was performed. Four patients with syndromic ectrodactyly had p63 heterozygous point mutations that affect the DNA binding domain of the protein. One of these subjects exhibited the typical features of EEC syndrome as well as ankyloblepharon being, to our knowledge, the first case combining these traits. This finding supports the view of a clinical overlap in this group of autosomal dominant syndromes caused by p63 mutations and demonstrates that there are exceptions in the previously established p63 genotype-phenotype correlation.

Adult↗