[Extensive hypodontia and other developmental defects in 2 generations of the same family].
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Adult↗
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Results for “ECTODERMAL DEFECT”
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Subcellular effects of experimental oligohydramnios on the developing rat limb.
In the rat, the development of the limb bud can be impaired by amniotic puncture. Selective haemorrhages are observed within 1 hour of the treatment. An ultrastructural analysis was undertaken to uncover the cytological changes associated with these haemorrhages. The earliest effect of oligohydramnios is the appearance of a periendothelial oedema which separates the mesodermal cellular processes from the endothelial basal lamina. The loosening of the latter and the distortion of the endothelial cells occur almost simultaneously. Subsequent damage of the mesodermal cells ensues, the ectoderm and the preskeletal condensations remaining unaffected. Only general damage of the embryo affecting all tissues will lead to the complete necrosis of the limb bud and even to foetal death. The great variability of skeletal defects observed in amniocentesis syndrome can be accounted for by the higher resistance of the differentiating cells to a decrease in blood supply.
Amniocentesis↗
Analysis of Msx1; Msx2 double mutants reveals multiple roles for Msx genes in limb development.
The homeobox-containing genes Msx1 and Msx2 are highly expressed in the limb field from the earliest stages of limb formation and, subsequently, in both the apical ectodermal ridge and underlying mesenchyme. However, mice homozygous for a null mutation in either Msx1 or Msx2 do not display abnormalities in limb development. By contrast, Msx1; Msx2 double mutants exhibit a severe limb phenotype. Our analysis indicates that these genes play a role in crucial processes during limb morphogenesis along all three axes. Double mutant limbs are shorter and lack anterior skeletal elements (radius/tibia, thumb/hallux). Gene expression analysis confirms that there is no formation of regions with anterior identity. This correlates with the absence of dorsoventral boundary specification in the anterior ectoderm, which precludes apical ectodermal ridge formation anteriorly. As a result, anterior mesenchyme is not maintained, leading to oligodactyly. Paradoxically, polydactyly is also frequent and appears to be associated with extended Fgf activity in the apical ectodermal ridge, which is maintained up to 14.5 dpc. This results in a major outgrowth of the mesenchyme anteriorly, which nevertheless maintains a posterior identity, and leads to formation of extra digits. These defects are interpreted in the context of an impairment of Bmp signalling.
Animals↗
Progeroid syndrome with facial teleangiectatic erythema, posterior subcapsular cataracts, calcification of basal ganglia and atrium septum defect type 2.
In this report we present the long-term follow-up findings in a young female born to consanguineous parents with the unique association of (1) a progeroid syndrome, (2) facial dysmorphism with relative microcephaly, triangular face, retrognathism and skin erythema, (3) bilateral posterior cataracts, (4) basal ganglia calcifications and (5) atrium septum defect type 2. Intelligence is borderline. Clinical evolution after normal puberty was positive with regression of the facial erythematous changes. Over the years differential diagnosis included progeria, hypohidrotic ectodermal dysplasia, Rothmund-Thompson syndrome, Cockayne syndrome, Bloom syndrome, but the clinical spectrum of abnormalities and the evolution with age were not compatible with one of these diagnoses. Parental consanguinity is in favour of autosomal recessive inheritance.
Abnormalities, Multiple↗
Aire downregulates multiple molecules that have contradicting immune-enhancing and immune-suppressive functions.
Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a systemic disease with autoimmune characteristics caused by mutations in a single gene called AIRE. Although a defect in negative selection has been emphasized for the pathogenesis of the autoimmune symptoms on the basis of studies of Aire-targeted mice, the function of the gene in the peripheral immune system and the cause of immunodeficiency noted in the disease have not been clarified yet. In this study, we demonstrated using murine Aire transfectants that Aire downregulates IL-1 receptor antagonist (IL-1Ra), which is important for immune suppression, and major histocompatibility complex (MHC) class II molecules, which are critical for acquired immunity. It was surprising to learn that Aire, which has been supposed to positively regulate transcription, downregulates multiple molecules. This downregulation of IL-1Ra and MHC class II molecules seems to be caused by the competition for transcriptional coactivator, CREB-binding protein (CBP), and may explain part of the contradictory (i.e., both autoimmune and immunodeficient) nature of APECED.
Animals↗
Towards subtlety: understanding the role of Toll-like receptor signaling in susceptibility to human infections.
Recent years have seen a dramatic improvement in our understanding of the role of innate immunity, and particularly Toll-like receptor (TLR) signaling, in human host defense. Appreciation of how defects in human TLR signaling enhance susceptibility to infection began with the identification of patients with monogenic immunodeficiencies, such as hypohydrotic ectodermal dysplasia with immunodeficiency and IRAK4 deficiency. Empowered by technological advances in genotyping and bioinformatics, we are now beginning to appreciate how common genetic variation in the genes controlling the innate immune response alters infectious susceptibility in a subtle but specific fashion. This review highlights the mechanisms of infectious susceptibility that result from complex interactions between the genetically variable host and microbe and explores how this new knowledge may ultimately translate into better care for our patients.
Disease Susceptibility↗
Identification of vitamin D receptor as a target of p63.
p63, a p53 homolog has been shown to play a role in development and cancer. p63 is essential for both commitment of ectoderm to stratified epithelia and for the proliferative potential of epithelial stem cells. p63 knockout mice are born with severe development defects and lack organs of epithelial origin. In addition, p63 has also been shown to play a role in cancer development through the differential regulation of genes with tumor suppressor function and genes involved in metastasis. In order to understand the role of p63 in cancer and development, genes that are specifically regulated by p63 but not p53 were identified. In this study, we provide evidence that p63gamma specifically upregulates vitamin D Receptor (VDR). In contrast, p53 does not appear to be involved in upregulation of VDR expression. Additionally, we demonstrate that a naturally occurring p63 missense mutant, p63gamma (R279H) and p14(ARF), both act in a dominant negative manner to inhibit p63gamma-mediated upregulation of VDR. Furthermore, using chromatin immunoprecipitation assays, we demonstrated that p63 directly binds to the VDR promoter in vivo. Our findings clearly demonstrate that VDR is a direct target of p63 and suggests that p63 may play a role in cancer and differentiation through modulation of the VDR pathway.
Bone Neoplasms↗
The tumor suppressor SMAD4/DPC4 is essential for epiblast proliferation and mesoderm induction in mice.
Members of the transforming growth factor (TGF)-beta superfamily have been shown to play a variety of important roles in embryogenesis, including dorsal and ventral mesoderm induction. The tumor suppressor SMAD4, also known as DPC4, is believed to be an essential factor that mediates TGF-beta signals. To explore functions of SMAD4 in development, we have mutated it by truncating its functional C-domain. We show that Smad4 is expressed ubiquitously during murine embryogenesis. Mice heterozygous for the Smad4(ex8/+) mutation are developmentally normal, whereas homozygotes die between embryonic day 6.5 (E6.5) and 8.5. All Smad4(ex8/ex8) mutants are developmentally delayed at E6 and show little or no elongation in the extraembryonic portion of late egg cylinder stage embryos. Consistent with this, cultured Smad4(ex8/ex8) blastocyst outgrowths suffer cellular proliferation defects and fail to undergo endoderm differentiation. Although a portion of mutant embryos at E8.5 show an increase in the embryonic ectoderm and endoderm, morphological and molecular analyses indicate that they do not form mesoderm. Altogether, these data demonstrate that SMAD4-mediated signals are required for epiblast proliferation, egg cylinder formation, and mesoderm induction.
Animals↗
Encephalocraniocutaneous lipomatosis.
Encephalocraniocutaneous lipomatosis is a distinct clinical syndrome characterized by unilateral cerebral malformations and ipsilateral scalp, face, and eye lesions. The cutaneous lesions are confined to the head. The central nervous system lesions consist in part of cerebral hemiatrophy, porencephaly, and defective opercularization of the insula. The intracranial lesions and clinical symptomatology are progressive, and appear, in part, to have a vascular pathogenesis. This suggests that a primary defect in the formation of tissues derived from embryonic mesenchyme may be responsible for the syndrome and that tissues derived from ectoderm may be secondarily affected.
Adolescent↗
Developmental mechanism involved in the embryonic reduction of limbs in reptiles.
The purpose of the studies here reported was to explain the mechanisms responsible for the reduction of limbs in the serpentiform reptiles. Descriptive and experimental embryology, ultrastructural studies, chemical action (with Ara-C) on embryos and (3H) thymidine autoradiography of limb buds were used in this study; they provide evidence that defects in the morphogenetic mechanisms involved in the development of limbs (somitic deficiency, incomplete differentiation and premature degeneration of the apical ectodermal ridge) are responsible for the cessation of growth of the limb buds in these reptiles. At the biochemical level, a strong decline in the rate of DNA synthesis in the mesodermal cells of the limb bud (during and after the degeneration of the apical ridge) is the main causative factor of the evolutionary arrest of limb development in serpentiform reptiles.
Animals↗
Autosomal dominant ectodermal dysplasia.
A three generation family with hypohidrotic ectodermal dysplasia (ED) is presented. Attempts to categorize the disorder in the family as one of the recognized types of ED were unsuccessful. Affected members of the family have mild hypotrichosis, mild hypodontia, and variable degrees of hypohidrosis. Autosomal dominant inheritance is proposed. Scanning electron microscopy on the hair of members of the family is presented. While there is no specific pattern of defects of the hair of affected persons, the cuticular layer is defective and there are longitudinal grooves in the hair shafts.
Child, Preschool↗
Specific NEMO mutations impair CD40-mediated c-Rel activation and B cell terminal differentiation.
Hypomorphic mutations in the zinc finger domain of NF-kappaB essential modulator (NEMO) cause X-linked hyper-IgM syndrome with ectodermal dysplasia (XHM-ED). Here we report that patient B cells are characterized by an absence of Ig somatic hypermutation (SHM) and defective class switch recombination (CSR) despite normal induction of activation-induced cytidine deaminase (AID) and Iepsilon-Cepsilon transcripts. This indicates that AID expression alone is insufficient to support neutralizing antibody responses. Furthermore, we show that patient B cells stimulated with CD40 ligand are impaired in both p65 and c-Rel activation, and whereas addition of IL-4 can enhance p65 activity, c-Rel activity remains deficient. This suggests that these NF-kappaB components have different activation requirements and that IL-4 can augment some but not all NEMO-dependent NF-kappaB signaling. Finally, using microarray analysis of patient B cells we identified downstream effects of impaired NF-kappaB activation and candidate factors that may be necessary for CSR and SHM in B cells.
Adolescent↗
The homeobox gene Hex is required in definitive endodermal tissues for normal forebrain, liver and thyroid formation.
The homeobox gene Hex is expressed in the anterior visceral endoderm (AVE) and rostral definitive endoderm of early mouse embryos. Later, Hex transcripts are detected in liver, thyroid and endothelial precursor cells. A null mutation was introduced into the Hex locus by homologous recombination in embryonic stem cells. Hex mutant embryos exhibit varying degrees of anterior truncation as well as liver and thyroid dysplasia. The liver diverticulum is formed but migration of hepatocytes into the septum transversum fails to occur. Development of the thyroid is arrested at the thyroid bud stage at 9.5 dpc. Brain defects are restricted to the rostral forebrain and have a caudal limit at the zona limitans intrathalamica, the boundary between dorsal and ventral thalamus. Analysis of Hex(-/-) mutants at early stages shows that the prospective forebrain ectoderm is correctly induced and patterned at 7.5 days post coitum (dpc), but subsequently fails to develop. AVE markers are expressed and correctly positioned but development of rostral definitive endoderm is greatly disturbed in Hex(-/-) embryos. Chimeric embryos composed of Hex(-/-) cells developing within a wild-type visceral endoderm show forebrain defects indicating that Hex is required in the definitive endoderm. All together, these results demonstrate that Hex function is essential in definitive endoderm for normal development of the forebrain, liver and thyroid gland.
Animals↗
Folic acid prevents exencephaly in Cited2 deficient mice.
Cited2 (also Mrg1/p35srj) is a member of a new conserved gene family that is expressed during mouse development and in adult tissues. In order to investigate the function of Cited2 during mouse embryogenesis, we introduced a null mutation into the Cited2 locus. Cited2(-/-) mutants died at late gestation and exhibited heart defects and exencephaly, arising from defective closure of the midbrain (MB) and hindbrain. Initiation of neural tube closure at the forebrain-midbrain (FB-MB) boundary, an essential step for closure of the cranial neural tube, was impaired in the Cited2(-/-) mutants. Gene marker analysis using in situ hybridization revealed that the patterning of the anterior neural plate and head mesenchyme was little affected or normal in the Cited2(-/-) embryos. However, Cited2 was required for the survival of neuroepithelial cells and its absence led to massive apoptosis in dorsal neuroectoderm around the FB-MB boundary and in a restricted transverse domain in the hindbrain. Treatment with folic acid significantly reduced the exencephalic phenotype in the Cited2(-/-) embryos both in vivo and in vitro. However, assessment of folate metabolism revealed no defect in the Cited2(-/-) mutants, and the elevated apoptosis observed in the neuroepithelium of the Cited2(-/-) mutants was apparently not decreased by folic acid supplementation. To our knowledge, the Cited2 mouse represents the first genetic model in which folic acid can prevent a defect in neural tube closure by a mechanism other than the neutralization of a defect in folate homeostasis.
Animals↗
CONGENITAL SCALP DEFECTS IN TWIN SISTERS.
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Congenital Abnormalities↗
Notch1 and 2 cooperate in limb ectoderm to receive an early Jagged2 signal regulating interdigital apoptosis.
Spontaneous and engineered mutations in the Notch ligand Jagged2 produced the Syndactylism phenotype (Jiang, R.L., Lan, Y., Chapman, H.D., Shawber, C., Norton, C.R., Serreze, D.V., Weinmaster, G., Gridley, T., 1998. Defects in limb, craniofacial, and thymic Development in Jagged2 mutant mice. Genes Dev. 12, 1046-1057; Sidow, A., Bulotsky, M.S., Kerrebrock, A.W., Bronson, R.T., Daly, M.J., Reeve, M.P., Hawkins, T.L., Birren, B.W., Jaenisch, R., Lander, E.S., 1997. Serrate2 is disrupted in the mouse limb-development mutant syndactylism. Nature 389, 722-725). Given that additional ligands may be expressed in the developing limb bud, it was possible that loss of Jagged2 disabled only part of Notch function in the limb. In addition, it is not clear from the expression pattern of Jagged2 in the apical ectodermal ridge (AER) whether the ectodermal or mesenchymal compartment of the limb bud receives the Jagged2 signal. To elucidate the requirement for the Notch pathway in limb development, we have analyzed single and compound Notch receptor mutants as well as gamma-secretase-deficient limbs. Floxed alleles were removed either from the developing limb bud ectoderm (using Msx2-Cre) or from the mesenchyme (using Prx1-Cre). Our results confirm that Jagged2 loss describes the contribution of the entire Notch pathway to the mouse limb development and revealed that both Notch1 and 2 are required in the ectoderm to receive the Jagged2 signal. Interestingly, our allelic series allowed us to determine that Notch receives this signal at an early stage in the developmental process and that memory of this event is retained by the mesenchyme, where Notch signaling appears to be dispensable. Thus, Notch signaling plays a non-autonomous role in digit septation.
Animals↗
[A family with the EEC syndrome (ectrodactily, ectodermal dysplasia clefting syndrome): clinical variability and genetic counseling].
In a family with segregation of EEC-Syndrome we observed five children--two girls and three males--(two of them dizygotic twins) affected by very various phenotypes of the syndrome. The ocular symptomatology was represented by agenesis or stenosis of lacrimal ducts: two children were operated, the other suffered from frequent inflammations. The study of the family suggest an autosomic dominant heredity with defect of penetrance on the father.
Abnormalities, Multiple↗
Refined mapping of Naegeli-Franceschetti- Jadassohn syndrome to a 6 cM interval on chromosome 17q11.2-q21 and investigation of candidate genes.
Naegeli-Franceschetti-Jadassohn syndrome and dermatopathia pigmentosa reticularis are autosomal dominant ectodermal dysplasias characterized by the absence of dermatoglyphics, reticulate hyper pigmentation of the skin, hypohidrosis, and heat intolerance. Palmoplantar keratoderma, nail dystrophy, and enamel defects are common in Naegeli-Franceschetti-Jadassohn syndrome, whereas diffuse alopecia is only seen in dermatopathia pigmentosa reticularis. We studied a large Swiss family with Naegeli-Franceschetti-Jadassohn syndrome originally described by Naegeli in 1927 and assessed linkage to chromosome 17q, which was proposed to harbor the Naegeli-Franceschetti-Jadassohn syndrome gene. Our results considerably narrow the Naegeli-Franceschetti-Jadassohn syndrome gene region from 27 cM to 6 cM flanked by D17S933 and D17S934 with a maximum multipoint LOD score of 2.7 at marker locus D17S800. In addition, we studied a small family with dermatopathia pigmentosa reticularis, and our linkage data suggest that dermatopathia pigmentosa reticularis may map to the same chromosomal region. The Naegeli-Franceschetti-Jadassohn syndrome critical interval spans approximately 5.4 Mb and contains a minimum of 45 distinct genes. We scrutinized 13 new prime candidates in addition to five genes previously examined, established the genomic organization of 10 of these genes, and excluded all of them by mutation analysis. Moreover, we identified a cDNA (KRT24) encoding a new keratin protein that bears high similarity to the type I keratins and displays a unique expression profile. No pathogenic mutations were identified in this novel gene either, however. In summary, our results substantially refine the Naegeli-Franceschetti-Jadassohn syndrome region and will aid in identifying a gene that is critical for ontogenesis of multiple ectodermal tissues.
Amino Acid Sequence↗