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PubMed1999

Requirement of SpOtx in cell fate decisions in the sea urchin embryo and possible role as a mediator of beta-catenin signaling.

We show here that the homeodomain transcription factor SpOtx is required for endoderm and aboral ectoderm formation during sea urchin embryogenesis. SpOtx target genes were repressed by fusing the SpOtx homeodomain to an active repression domain of Drosophila Engrailed. The Engrailed-SpOtx fusion protein reduced the expression of endoderm- and aboral ectoderm-specific genes and inhibited the formation of endoderm and aboral ectoderm cell types. Coexpressing activated beta-catenin with Engrailed-SpOtx did not overcome the inhibition of endoderm and aboral ectoderm formation, suggesting that SpOtx functioned either downstream of or parallel to nuclear beta-catenin. Embryos expressing C-cadherin, which blocks nuclear translocation of beta-catenin, have defects in endoderm and aboral ectoderm formation. Coexpressing SpOtx with C-cadherin restored aboral ectoderm-specific gene expression and aboral ectoderm morphology, but with C-cadherin present, SpOtx was not sufficient for endoderm formation. Our results show that SpOtx plays a key role in the activation of aboral ectoderm- and endoderm-specific gene expression and, in addition, suggest that SpOtx mediates some of beta-catenin's functions in endoderm and aboral ectoderm formation.

Animals↗
PubMed2000

[Pigmentosum retinis and tubulo-interstitial nephronophtisis in Sensenbrenner syndrome: a case report].

PURPOSE: Sensenbrenner syndrome or cranio-ectodermal dysplasia is an extremely rare autosomal recessive condition (12 cases reported in literature). Our observation shows the possibility of both ocular and renal involvement associated with cranio-ectodermal abnormalities. PATIENTS: and method:We report the case of a girl who presented a typical cranio-ectodermal syndrome with dolicocephaly, short thorax, short limbs, short fingers and teeth abnormalities. At five years, she was found to have pigmentosum retinitis with amblyopy and moderate hyperopia. A chronic renal failure with uncontrollable hypertension underwent a cadaveric-donor transplantation at the age of six years. RESULTS: Two years later, the pigmentosum retinitis was stable. The kidney histology revealed a tubulo-interstitial nephronophtisis. The molecular analysis of the NPH 1 locus, which was associated with nephronophtisis, was negative. DISCUSSION: Our observation and two recent publications have in common ocular and renal abnormalities associated with cranio-ectodermal dysplasia. The underlying genetic defect would involve not only morphogenesis but also development and maturation of organs as eye and kidney. Sensenbrenner syndrome would thus be similar to certain disorders affecting the eye, kidney, skeleton and ectodermal structures such as the EEM, Senior-Loken, Mainzer-Saldino, and Jeune syndromes. CONCLUSION: The retinal dystrophy falls within the spectrum of clinical and genetic forms of pigmentosum retinitis. Our observation would confirm possible links between Sensenbrenner syndrome and oculorenal syndromes.

Abnormalities, Multiple↗
PubMed1996

Alternate functions of the single-minded and rhomboid genes in development of the Drosophila ventral neuroectoderm.

We have investigated the roles of the single-minded (sim) and rhomboid (rho) genes in generating distinct cell fates in the Drosophila embryonic neuroectoderm. We show that sim functions to repress ventral ectodermal cell fates, as in sim mutants mesectodermal cells adopt the fates of neighboring ventral ectodermal cells and targeted sim expression in P[paired.Gal4]/P[UAS-sim] embryos results in loss of epidermal cells. We also find that rho is not required for early expression of sim or ventral nervous system defective in mesectodermal or ventral ectodermal cells; targeted rho expression in P[paired-Gal4]/P[UAS-rho] embryos results in lateral-to-ventral cell fate shifts in the developing neuroectoderm; and midline-targeted rho expression can rescue the medial denticle fusions in rho mutant cuticles.

Animals↗
PubMed1999

Mini-review: toward understanding mechanisms of genetic neural tube defects in mice.

We review the data from studies of mouse mutants that lend insight to the mechanisms that lead to neural tube defects (NTDs). Most of the 50 single-gene mutations that cause neural tube defects (NTDs) in mice also cause severe embryonic-lethal syndromes, in which exencephaly is a nonspecific feature. In a few mutants (e.g., Trp53, Macs, Mlp or Sp), other defects may be present, but affected fetuses can survive to birth. Multifactorial genetic causes, as are present in the curly tail stock (15-20% spina bifida), or the SELH/Bc strain (15-20% exencephaly), lead to nonsyndromic NTDs. The mutations indicate that "spina bifida occulta," a dorsal gap in the vertebral arches over an intact neural tube, is usually genetically and developmentally unrelated to exencephaly or "spina bifida" (aperta). Almost all exencephaly or spina bifida aperta of genetic origin is caused by failure of neural fold elevation. The developmental mechanisms in genetic NTDs are considered in terms of distinct rostro-caudal zones along the neural folds that likely differ in mechanism of elevation. Failure of elevation leads to: split face (zone A), exencephaly (zone B), rachischisis (all of zone D), or spina bifida (caudal zone D). The developmental mechanisms leading to these genetic NTDs are heterogeneous, even within one zone. At the tissue level, the mutants show that the mechanism of failure of elevation can involve, e.g., (1) slow growth of adjacent tethered tissue (curly tail), (2) defective forebrain mesenchyme (Cart1 or twist), (3) defective basal lamina in surface ectoderm (Lama5), (4) excessive breadth of floorplate and notochord (Lp), (5) abnormal neuroepithelium (Apob, Sp, Tcfap2a), (6) morphological deformation of neural folds (jmj), (7) abnormal neuroepithelial and neural crest cell gap-junction communication (Gja1), or (8) incomplete compensation for a defective step in the elevation sequence (SELH/Bc). At the biochemical level, mutants suggest involvement of: (1) faulty regulation of apoptosis (Trp53 or p300), (2) premature differentiation (Hes1), (3) disruption of actin function (Macs or Mlp), (4) abnormal telomerase complex (Terc), or (5) faulty pyrimidine synthesis (Sp). The NTD preventative effect of maternal dietary supplementation is also heterogeneous, as demonstrated by: (1) methionine (Axd), (2) folic acid or thymidine (Sp), or (3) inositol (curly tail). The heterogeneity of mechanism of mouse NTDs suggests that human NTDs, including the common nonsyndromic anencephaly or spina bifida, may also reflect a variety of genetically caused defects in developmental mechanisms normally responsible for elevation of the neural folds.

Animals↗
PubMed2000

Ellis van Creveld syndrome (chondroectodermal dysplasia, MIM 22550) in three siblings from a non-consanguineous mating.

The major diagnostic features of Ellis van Creveld syndrome (EvC) includes disproportionate short stature, polydactyly, ectodermal anomalies, and structural heart defects. We describe three siblings with EvC of a non-consanguineous mating. The history of these siblings well illustrate the clinical manifestations and complications that children with EvC encounter. All three girls had short stature, narrow rib cage, polydactyly and nail hypoplasia. The first daughter died in early infancy in respiratory failure. The second daughter underwent open heart surgery for atrial septal defect repair. The third daughter, diagnosed in utero with fetal ultrasonography, currently is scheduled for surgical excision of extra-digits and extraction of neonatal teeth. Infant mortality rates among patients with EvC is strikingly high due primarily to cardiorespiratory failure. If they survive infancy morbidity is significant. The gene effected in individuals with EvC has recently been identified on the short arm of chromosome 4. Future testing for gene mutations may provide valuable information for premarital counseling and prenatal diagnosis. Three offspring with disproportionate short stature, polydactyly, and ectodermal dysplasia of a non-consanguineous mating, strongly indicate parental heterozygosity for Ellis van Creveld syndrome.

Adult↗
PubMed2007

A defect of regulatory T cells in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), a monogenic recessive disease characterized by autoimmunity against multiple tissues, offers a unique possibility to study the breakdown of self-tolerance in humans. It is caused by mutations in the autoimmune regulator gene (AIRE), which encodes a transcriptional regulator. Work using Aire(-/-) mice suggests that Aire induces ectopic expression of peripheral Ags and promotes their presentation in the thymus. We have explored reasons for the difference between the comparatively mild phenotype of Aire-deficient mice and human APECED patients. We provide evidence that, unlike in the Aire(-/-) mice, in the patients a key mediator of active tolerance, the CD4(+)CD25(+) regulatory T (Treg) cell subset is impaired. This was shown by significantly decreased expression of FOXP3 mRNA and protein, decreased function, and alterations in TCR repertoire. Also, in the normal human thymus a concentric accumulation of AIRE(+) cells was seen around thymic Hassall's corpuscles, suggesting that in the patients these cells may be involved in the observed Treg cell failure. In Aire(-/-) mice the expression of FoxP3 was normal and even increased in target tissues in parallel with the lymphocyte infiltration process. Our results suggest that a Treg cell defect is involved in the pathogenesis of APECED and emphasize the importance of active tolerance mechanisms in preventing human autoimmunity.

Adult↗
PubMed1994

Thymic hypoplasia and T-cell deficiency in ectodermal dysplasia: case report and review of the literature.

Ectodermal dysplasia is a heterogeneous disorder that includes a constellation of congenital malformations occasionally associated with mild to moderate immune dysfunction. In this report, we describe a female infant with ectodermal dysplasia who was found to have thymic hypoplasia but no other phenotypic features of the DiGeorge anomalad. She experienced Candida parapsilosis sepsis at 1 week of age and a skin infection with Mycobacterium chelonii at 6 months. The numbers of blood B cells were normal and serum immunoglobulins normal to slightly reduced, but serum antibody responses of all immunoglobulin isotypes to protein immunogens were absent. Blood T cells were profoundly reduced and proliferative responses of T cells to mitogens were blunted. In contrast, there was an increased number of natural killer (NK) cells and increased NK activity in the blood. Over the first year of life, some of the immunodeficiencies resolved. Although the numbers of blood T cells (17% of total lymphocytes) remained low, proliferative responses to mitogens normalized and specific antibody responses improved. It seems likely that the thymic hypoplasia in this case was due to a paucity of ectodermal elements in the developing thymus, and that the immune defects were largely secondary to that event. In that respect, this human model of ectodermal dysplasia and thymic hypoplasia resembled the ectodermal/thymic defects found in the nude mouse.

Cell Line↗
PubMed1993

Cardio-facio-cutaneous (CFC) syndrome: neurological features in two children.

Cardio-facio-cutaneous (CFC) syndrome consists of heart defects, a characteristic facial appearance, ectodermal abnormalities, growth retardation and developmental delay. The authors report two children with this condition, drawing particular attention to the neurological manifestations. The neurological features are neuro-opthalmological findings such as strabismus, ptosis and nystagmus, cortical atrophy, ventriculomegaly, mental retardation, seizures and hypotonia. These manifestations may allow differentiation of CFC from Noonan syndrome, which shares many of the physical features, but not these neurological features.

Abnormalities, Multiple↗
PubMed1995

Interstitial deletion of the long arm of chromosome 6 associated with unusual limb anomalies: report of two new patients and review of the literature.

We report on unusual manifestations in 2 unrelated children with interstitial deletion of 6q, with nearly identical breakpoints of 6q16.2q23.1 and 6q16.3q22.3. Major findings include growth retardation, profound developmental delay, microcephaly, facial anomalies, sparse hair, congenital heart defects, and striking hand malformations. Discordant anomalies were duodenal atresia and hypoplastic genitalia in 1 child. Split-hand defect, polydactyly, gastrointestinal anomalies, and ectodermal dysplasia have not been described previously in children with 6q deletion. The presence of hand malformations in 2 children with similar deletion breakpoints strongly suggests that this is a candidate region for one or more genes involved in limb development. Comparison of the clinical findings of other patients with 6q2 deletion suggests a recognizable phenotype.

Chromosome Banding↗
PubMed1995

[The clinical spectrum of focal dermal hypoplasia].

Focal dermal hypoplasia (FHD) is an X chromosomal dominant inherited disease with unknown gene defect. FDH is characterized by ectodermal and mesodermal malformations. It is thought to be lethal in males; however, males may survive as mosaics or possibly as Klinefelter syndrome (XXY). When mosaicism involves the gonads the disease may be transmitted from father to child. In females, the abnormal phenotype is thought to be expressed in a blaschkoid pattern because of random X chromosome inactivation. We have collected eight cases of which three were males. We present the typical clinical dermatological feature and draw attention to cases with minimal skin involvement.

Adolescent↗
PubMed1980

Urinary tract infection with atypical mycobacteria.

We present a case of disseminated atypical mycobacterial (Mycobacterium intracellularis) infection of the urinary tract. The patient had anhydrous ectodermal dysplasia and an unrelated defect in cell-mediated immunity. The infection resulted in a lengthy ureteral stricture with resultant hydronephrosis and diminished kidney function. A review of the literature revealed only 13 previous cases of atypical mycobacterial infection of the urinary tract. It is important to distinguish between simple colonization by these organisms and actual infection. Differentiation between atypical mycobacterial infection and urinary tuberculosis is important in determining the therapeutic regimen.

Adolescent↗
PubMed1997

Unilateral somatic and intracranial hypoplasia.

We report on clinical and MR findings in a woman with a peculiar disease. She was studied from childhood to adulthood. She showed several anomalies affecting structures of ectodermal and mesodermal origin. Specific defects included right cerebral and cerebellar hypoplasia, right cerebral cortical polymicrogyria, agenesis of the corpus callosum, right micro-ophthalmia and cataract, right breast hypoplasia, right upper and lower extremity hypoplasia, bilateral acral alterations affecting especially the middle phalanges, left hemifacial hypoplasia (probably secondary to the severe contralateral cerebral hemisphere lesion), mental retardation and partial epilepsy. MR disclosed right cerebral and cerebellar hypoplasia, right cerebral cortical polymicrogyria, agenesis of corpus callosum and right micro-ophthalmia. She did not exhibit either orbital cysts or cutaneous abnormalities. The complex symptomatology of unknown origin presented by this patient suggests a new developmental malformation consisting in hypoplasia of a complete hemibody.

Abnormalities, Multiple↗
PubMed1984

Dental features in congenital persistent renal tubular acidosis of proximal type.

The dental features in a hitherto unknown type of renal tubular acidosis (capillary blood pH 7.07-7.15) of proximal type are reported. The patient presented agenesis of three second premolars, delayed development and eruption of permanent teeth, delayed shedding of the primary dentition and severe enamel hypoplasia of the permanent teeth. Apart from exceptionally thin enamel, histologic, fluorescent and polarization microscopic and microradiographic investigation of three primary teeth did not reveal unusual findings. The changes are most probably due to a generalized, acidosis-induced defect in several highly differentiated ectodermal tissues.

Acidosis, Renal Tubular↗
PubMed2005

AIRE deficiency in thymus of 2 patients with Omenn syndrome.

Omenn syndrome is a severe primary immunodeficiency with putative autoimmune manifestations of the skin and gastrointestinal tract. The disease is caused by hypomorphic mutations in recombination-activating genes that impair but do not abolish the process of VDJ recombination, leading to the generation of autoreactive T cells with a highly restricted receptor repertoire. Loss of central tolerance in genetically determined autoimmune diseases, e.g., autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, is associated with defective expression by medullary thymic epithelial cells of AIRE, the transcription activator that induces thymic expression of tissue-specific antigens. Analysis of AIRE expression in the thymi of 2 Omenn syndrome patients and 1 SCID patient, by real-time RT-PCR and immunohistochemistry, demonstrated a profound reduction in the levels of AIRE mRNA and protein in patients as compared with a normal control subject. Lack of AIRE was associated with normal or even increased levels of keratin and lymphotoxin-beta receptor mRNAs, while mRNAs of the self-antigens insulin, cytochrome P450 1a2, and fatty acid-binding protein were undetectable in thymi from immunodeficiency patients. These results demonstrate that deficiency of AIRE expression is observed in severe immunodeficiencies characterized by abnormal T cell development and suggest that in Omenn syndrome, the few residual T cell clones that develop may escape negative selection and thereafter expand in the periphery, causing massive autoimmune reactions.

Animals↗
PubMed2006

Epidermal and craniofacial defects in mice overexpressing Klf5 in the basal layer of the epidermis.

Krüppel-like factor5 (Klf5) is a zinc-finger transcription factor normally expressed in the skin. Here, we show that overexpression of Klf5 in the basal layer of the epidermis during embryogenesis affects epidermal development and disrupts epithelial-mesenchymal interactions necessary for skin adnexae formation as well as craniofacial morphogenesis. The transgenic mice exhibited exencephaly, craniofacial defects, persistent abdominal herniation and ectodermal dysplasia. Moreover, the epidermis was hypoplastic and underwent abnormal differentiation with expression of keratin8, a marker for single-layered epithelia, in the stratified epidermis. Correspondingly, we observed a downregulation of DeltaNp63 expression in the skin. Overexpression of Klf5 in adult mice led to hyperkeratosis, follicle occlusion and epidermal erosions. Further, we observed decrease and even loss of the stem cell population of bulge keratinocytes, as characterized by the expression pattern of alpha6 integrin and CD34 markers. Our data suggest a new role of Klf5 as a modulator of p63 expression and the differentiation program of epidermal cells relevant for regenerative potential of the epidermis and epithelial-mesenchymal interactions.

Animals↗
PubMed1994

Expression of three mouse homologs of the Drosophila segment polarity gene cubitus interruptus, Gli, Gli-2, and Gli-3, in ectoderm- and mesoderm-derived tissues suggests multiple roles during postimplantation development.

Three mouse genes, Gli, Gli-2, and Gli-3, which share a similar zinc finger domain with the products of the Drosophila segment polarity gene cubitus interruptus and the Caenorhabditis elegans sex-determining gene tra-1 were cloned and characterized. The expression patterns during postimplantation development of the three genes were analyzed by Northern blot, whole-mount, and section in situ hybridizations. Expression was first detected during gastrulation in both the ectoderm and mesoderm. Later in development, their expression became more restricted in various ectoderm- and mesoderm-derived tissues and was not detectable after completion of organogenesis. Interestingly, in the developing neural tube, Gli showed a narrow ventral domain of expression, whereas Gli-2 and Gli-3 showed a broad and dorsally restricted domain. Expression of these three Gli genes in various ectoderm- and mesoderm-derived tissues suggests that they play multiple roles during postimplantation development. Consistent with this hypothesis, a naturally occurring Gli-3 mutation, the mouse extra-toes mutant; shows defects in both mesoderm- and ectoderm-derived tissues.

Amino Acid Sequence↗
PubMed1978

[The EEC-syndrome. Case report and some suggestions about its pathogenesis (author's transl)].

The clinical data of a boy with ectrodactyly, ectodermal dysplasia, and cleft lip and palate (EEC-syndrome) are presented. Until now about 80 case histories with this syndrome have been published, 30 of them having all 3 symptoms. The combination of defects in rather different organs of ectodermal as well as mesodermal origin is difficult to understand. Changes in ectodermal tissues may well be the key factor in explaining the pathogenesis of this syndrome. This is supported by evidence gained by ontogenetical research with animals.

Child, Preschool↗