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At least 865 records · Page 48Linked to original sources
PubMed2000

Genomic amplification of the human plakophilin 1 gene and detection of a new mutation in ectodermal dysplasia/skin fragility syndrome.

Ectodermal dysplasia/skin fragility syndrome is a recently described autosomal recessive disease affecting skin, nails, and hair (MIM 604536), that results from mutations in plakophilin 1, a structural component of desmosomes. We report a new plakophilin 1 mutation in an affected patient as well as detailing the intron-exon organization of the gene to facilitate future polymerase chain reaction-based mutation screening. Using polymerase chain reaction amplification of genomic DNA, we identified 15 exons spanning approximately 50 kb. Direct sequencing disclosed several nonpathogenic intragenic polymorphisms, as well as a homozygous splice site mutation (1233-2 A-->T; GenBank Z73678) in a 17 y old affected male. The clinical features comprised skin erosions, dystrophic nails, sparse hair, and painful thickening and cracking of palms and soles. Skin biopsy showed negative immunolabeling with an anti-plakophilin 1 antibody and small desmosomes. These results expand the database of plakophilin 1 mutations and demonstrate the importance of this protein in the stabilization of desmosomal adhesion in terminally differentiating keratinocytes.

Adolescent↗
PubMedDate not supplied

Childhood vulval lichen sclerosus in a patient with ectodermal dysplasia and uncombable hair.

An 11-year-old girl was diagnosed as having ectodermal dysplasia, with abnormalities of her nails, teeth, and hair noted from infancy. Her hair was unruly and investigations confirmed the changes seen in "cheveux incoiffables"-the uncombable hair syndrome. She also had atopy requiring treatment to control asthma and eczema. When she was 8 years old she developed vulval lichen sclerosus, which was controlled easily with early treatment. The coexistence of these conditions is discussed.

Asthma↗
PubMed1990

[Dysgenesis of the neural crest, ectoderm, mesoderm and fetal alcohol syndrome].

A case is described having malformation of the anterior chamber with bilateral high IOP combined with multiple ocular anomalies in a 13-year-old girl. Here, embryotoxon posterius, synechiae out to Schwalbe's line, and hypoplasia of the iris stroma in the form of Rieger's anomaly are associated with: myelinated corneal nerves concurrent with appearance of vessels without scleralization, unilateral orbital hypoplasia without microphthalmia and without enophthalmos within the scope of a unilateral facial hypoplasia, bilateral epicanthus with asymmetry of the lid-openings without hypertelorism, bilateral delayed development of the tear ducts, horizontal myopic astigmatism and bilateral relative amblyopia, dental deformation, urogenital malformation, deformation of the joints, slightly delayed mental development, ataxia, normal karyotype. In a chronically alcoholic mother, the association between these systemic and ocular anomalies constitutes a fetal alcohol syndrome. Although the anomalies of other derivatives of the neural crest have already been described in this context, certain of these anomalies, such as malformations of the ectoderm or mesoderm, have not been reported.

Abnormalities, Multiple↗
PubMed1990

Clinical variation of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) in a series of 68 patients.

To define the clinical picture and course of the autosomal recessive disease called autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), we report data from our 10-month to 31-year follow-up of 68 patients from 54 families, now 10 months to 53 years of age. The clinical manifestations varied greatly and included from one to eight disease components, 63 percent of the patients having three to five of them. The initial manifestation was oral candidiasis in 41 patients (60 percent), intestinal malabsorption in 6 (9 percent), and keratopathy in 2 (3 percent). All the patients had candidiasis at some time. The earliest endocrine component appeared at 19 months to 35 years of age. Hypoparathyroidism was present in 54 patients (79 percent), adrenocortical failure in 49 (72 percent), and gonadal failure in 15 (60 percent) of the female patients greater than or equal to 13 years of age and 4 (14 percent) of the male patients greater than or equal to 16 years of age. There were multiple endocrine deficiencies in half the patients. From 4 to 29 percent of the patients had periodic malabsorption, gastric parietal-cell atrophy, hepatitis, alopecia, vitiligo, or a combination of these conditions. Dental-enamel hypoplasia and keratopathy were also frequent but were not attributable to hypoparathyroidism. In the patients whose initial manifestation (other than candidiasis) was adrenal failure, the other components developed less often than in the remaining patients. We conclude that the clinical spectrum in patients with APECED is broad. The majority of patients have three to five manifestations, some of which may not appear until the fifth decade. Therefore, all patients need lifelong follow-up for the detection of new components of the disease.

Adolescent↗
PubMed2001

Prosthetic treatments for patients with ectodermal dysplasia.

This article defines and describes the nature of ectodermal dysplasias, highlighting the dental complications associated with this congenital/developmental condition. A treatment protocol for meeting patients' functional and esthetic needs as they grow into adulthood is presented.

Adolescent↗
PubMed1999

X-ngnr-1 and Xath3 promote ectopic expression of sensory neuron markers in the neurula ectoderm and have distinct inducing properties in the retina.

Xath3 encodes a Xenopus neuronal-specific basic helix-loop-helix transcription factor related to the Drosophila proneural factor atonal. We show here that Xath3 acts downstream of X-ngnr-1 during neuronal differentiation in the neural plate and retina and that its expression and activity are modulated by Notch signaling. X-ngnr-1 activates Xath3 and NeuroD by different mechanisms, and the latter two genes crossactivate each other. In the ectoderm, X-ngnr-1 and Xath3 have similar activities, inducing ectopic sensory neurons. Among the sensory-specific markers tested, only those that label cranial neurons were found to be ectopically activated. By contrast, in the retina, X-ngnr-1 and Xath3 overexpression promote the development of overlapping but distinct subtypes of retinal neurons. Together, these data suggest that X-ngnr-1 and Xath3 regulate successive stages of early neuronal differentiation and that, in addition to their general proneural properties, they may contribute, in a context-dependent manner, to some aspect of neuronal identity.

Animals↗
PubMed1999

Functional characterization of the promoter of the X-linked ectodermal dysplasia gene.

Anhidrotic ectodermal dysplasia (EDA) is a disorder characterized by poor development of hair, teeth, and sweat glands, and results from lesions in the X-linked EDA gene. We have cloned a 1.6-kilobase 5'-flanking region of the human EDA gene and used it to analyze features of transcriptional regulation. Primer extension analysis located a single transcription initiation site 264 base pairs (bp) upstream of the translation start site. When the intact cloned fragment or truncated derivatives were placed upstream of a reporter luciferase gene and transfected into a series of cultured cells, expression comparable with that conferred by an SV40 promoter-enhancer was observed. The region lacks a TATA box sequence, and basal transcription from the unique start site is dependent on two binding sites for the Sp1 transcription factor. One site lies 38 bp 5' to the transcription start site, in a 71-bp sequence that is sufficient to support up to 35% of maximal transcription. The functional importance of the Sp1 sites was demonstrated when cotransfection of an Sp1 expression vector transactivated the EDA promoter in the SL2 Drosophila cell line that otherwise lacks endogenous Sp1. Also, both Sp1 binding sites were active in footprinting and gel shift assays in the presence of either crude HeLa cell nuclear extract or purified Sp1 and lost activity when the binding sites were mutated. A second region involved in positive control was localized to a 40-bp sequence between -673 and -633 bp. This region activated an SV40 minimal promoter 4- to 5-fold in an orientation-independent manner and is thus inferred to contain an enhancer region.

Base Sequence↗
PubMed2001

Mutations leading to X-linked hypohidrotic ectodermal dysplasia affect three major functional domains in the tumor necrosis factor family member ectodysplasin-A.

Mutations in the epithelial morphogen ectodysplasin-A (EDA), a member of the tumor necrosis factor (TNF) family, are responsible for the human disorder X-linked hypohidrotic ectodermal dysplasia (XLHED) characterized by impaired development of hair, eccrine sweat glands, and teeth. EDA-A1 and EDA-A2 are two splice variants of EDA, which bind distinct EDA-A1 and X-linked EDA-A2 receptors. We identified a series of novel EDA mutations in families with XLHED, allowing the identification of the following three functionally important regions in EDA: a C-terminal TNF homology domain, a collagen domain, and a furin protease recognition sequence. Mutations in the TNF homology domain impair binding of both splice variants to their receptors. Mutations in the collagen domain can inhibit multimerization of the TNF homology region, whereas those in the consensus furin recognition sequence prevent proteolytic cleavage of EDA. Finally, a mutation affecting an intron splice donor site is predicted to eliminate specifically the EDA-A1 but not the EDA-A2 splice variant. Thus a proteolytically processed, oligomeric form of EDA-A1 is required in vivo for proper morphogenesis.

Alternative Splicing↗
PubMed2005

NMR structure of the first PHD finger of autoimmune regulator protein (AIRE1). Insights into autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) disease.

Mutations in the autoimmune regulator protein AIRE1 cause a monogenic autosomal recessively inherited disease: autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). AIRE1 is a multidomain protein that harbors two plant homeodomain (PHD)-type zinc fingers. The first PHD finger of AIRE1 is a mutational hot spot, to which several pathological point mutations have been mapped. Using heteronuclear NMR spectroscopy, we determined the solution structure of the first PHD finger of AIRE1 (AIRE1-PHD1), and characterized the peptide backbone mobility of the domain. We performed a conformational analysis of pathological AIRE1-PHD1 mutants that allowed us to rationalize the structural impact of APECED-causing mutations and to identify an interaction site with putative protein ligands of the AIRE1-PHD1 domain. The structure unequivocally exhibits the canonical PHD finger fold, with a highly conserved tryptophan buried inside the structure. The PHD finger is stabilized by two zinc ions coordinated in an interleaved (cross-brace) scheme. This zinc coordination resembles RING finger domains, which can function as E3 ligases in the ubiquitination pathway. Based on this fold similarity, it has been suggested that PHD fingers might also function as E3 ligases, although this hypothesis is controversial. At variance to a previous report, we could not find any evidence that AIRE1-PHD1 has an intrinsic E3 ubiquitin ligase activity, nor detect any direct interaction between AIRE1-PHD1 and its putative cognate E2. Consistently, we show that the AIRE1-PHD1 structure is clearly distinct from the RING finger fold. Our results point to a function of the AIRE1-PHD1 domain in protein-protein interactions, which is impaired in some APECED mutations.

Amino Acid Sequence↗
PubMed2005

A point mutation in NEMO associated with anhidrotic ectodermal dysplasia with immunodeficiency pathology results in destabilization of the oligomer and reduces lipopolysaccharide- and tumor necrosis factor-mediated NF-kappa B activation.

The NEMO (NF-kappaB essential modulator) protein plays a crucial role in the canonical NF-kappaB pathway as the regulatory component of the IKK (IkappaB kinase) complex. The human disease anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) has been recently linked to mutations in NEMO. We investigated the effect of an alanine to glycine substitution found in the NEMO polypeptide of an EDA-ID patient. This pathogenic mutation is located within the minimal oligomerization domain of the protein, which is required for the IKK activation in response to diverse stimuli. The mutation does not dramatically change the native-like state of the trimer, but temperature-induced unfolding studied by circular dichroism showed that it leads to an important loss in the oligomer stability. Furthermore, fluorescence studies showed that the tyrosine located in the adjacent zinc finger domain, which is possibly required for NEMO ubiquitination, exhibits an alteration in its spectral properties. This is probably due to a conformational change of this domain, providing evidence for a close interaction between the oligomerization domain and the zinc finger. In addition, functional complementation assays using NEMO-deficient pre-B and T lymphocytes showed that the pathogenic mutation reduced TNF-alpha and LPS-induced NF-kappaB activation by altering the assembly of the IKK complex. Altogether, our findings provide understanding as to how a single point mutation in NEMO leads to the observed EDA-ID phenotype in relation to the NEMO-dependent mechanism of IKK activation.

Amino Acid Sequence↗
PubMed1995

Permeation properties of a Ca(2+)-blockable monovalent cation channel in the ectoderm of the chick embryo: pore size and multioccupancy probed with organic cations and Ca2+.

A Ca(2+)-blockable monovalent cation channel is present in the apical membrane of the ectoderm of the gastrulating chick embryo. We used the patch clamp technique to study several single-channel permeation properties of this channel. In symmetrical conditions without Ca2+, the Na+ current carried by the channel rectifies inwardly. The channel has an apparent dissociation constant for extracellular Na+ of 115 mM at 0 mV and a low density of negative surface charge (-0.03 e/nm2) at its extracellular entrance. The minimal pore diameter is approximately 5.8 A, as calculated from the relative permeabilities of 10 small organic cations. Extracellular application of six large organic cations decreased the inward Na+ current in a voltage-dependent manner, which strongly suggests an intrachannel block. The presence of at least two ion binding sites inside the pore is inferred from the Na+ dependence of the block by the organic cations. This hypothesis is strengthened by the fact that the extracellular Ca2+ block is also modified by the Na+ concentration. In particular, the rise of the unblocking rate with increased Na+ concentrations clearly suggests the presence of an interaction between Ca2+ and Na+ inside the channel. A low probability of double occupancy at physiological ionic conditions is implied from the absence of an anomalous mole fraction effect with mixtures of extracellular Li+ and K+. Finally, the absence of inward current at very strong hyperpolarizations and in the presence of 10 mM extracellular Ca2+ demonstrates the absence of significant Ca2+ current through this channel. It is argued that this embryonic epithelial Ca(2+)-blockable monovalent cation channel is related to both L-type Ca2+ channel and cyclic nucleotide-gated channels.

Animals↗
PubMed1998

Syndromic ectrodactyly with severe limb, ectodermal, urogenital, and palatal defects maps to chromosome 19.

Congenital limb malformations rank behind only congenital heart disease as the most common birth defects observed in infants. Finding genes that cause defects in human limb patterning should be straightforward but has been limited, in part, by the bewildering spectrum of phenotypes, which are difficult to separate into etiologically distinct disorders. One approach to the identification of relevant genes is to take advantage of unique extended kindreds in which a defect in limb patterning is segregating. Recently, a large Dutch family with ectrodactyly, ectodermal dysplasia, cleft palate, and urogenital defects (EEC) was described by Maas et al. We have studied this kindred and localized a gene causing EEC to a locus on chromosome 19, in a region defined by D19S894 and D19S416. A second extended kindred with EEC does not map to this locus, indicating that EEC is a genetically heterogeneous disorder. Growth and patterning of the limbs, teeth, hair, and genitourinary system are mediated in part by epithelial-mesenchyme inductive interactions. The identification of both the gene causing EEC and its mutation may further elucidate the general signals mediating inductive mechanisms.

Abnormalities, Multiple↗
PubMed1998

A gene for autosomal dominant hypohidrotic ectodermal dysplasia (EDA3) maps to chromosome 2q11-q13.

Autosomal dominant hypohidrotic ectodermal dysplasia (ADHED) is a disorder characterized by fine, slow-growing scalp and body hair, sparse eyebrows and eyelashes, decreased sweating, hypodontia, and nail anomalies. By genetic linkage analysis of a large ADHED kindred, we have mapped a gene for ADHED (EDA3) to the proximal long arm of chromosome 2 (q11-q13). Obligate recombinations localize EDA3 to an approximately 9-cM interval between D2S1321 and D2S308, with no apparent recombinations with markers D2S1343, D2S436, D2S293, D2S1894, D2S1784, D2S1890, D2S274, and CHLC.GAAT11C03.

Chromosomes, Human, Pair 2↗
PubMed1998

Linkage disequilibrium mapping of the gene for Margarita Island ectodermal dysplasia (ED4) to 11q23.

Margarita Island ectodermal dysplasia (ED4) is an autosomal recessive disorder characterized by unusual facies, dental anomalies, hypotrichosis, palmoplantar hyperkeratosis and onychodysplasia, syndactyly, and cleft lip/cleft palate. We have used an affected-only DNA-pooling strategy to carry out linkage disequilibrium mapping of the ED4 gene to 11q23. Haplotype analysis of four complex Margarita Island ED4 families localized the ED4 gene to an approximately 1-2-Mb interval spanned by just two YACs.

Chromosome Mapping↗
PubMed2006

Naegeli-Franceschetti-Jadassohn syndrome and dermatopathia pigmentosa reticularis: two allelic ectodermal dysplasias caused by dominant mutations in KRT14.

Naegeli-Franceschetti-Jadassohn syndrome (NFJS) and dermatopathia pigmentosa reticularis (DPR) are two closely related autosomal dominant ectodermal dysplasia syndromes that clinically share complete absence of dermatoglyphics (fingerprint lines), a reticulate pattern of skin hyperpigmentation, thickening of the palms and soles (palmoplantar keratoderma), abnormal sweating, and other subtle developmental anomalies of the teeth, hair, and skin. To decipher the molecular basis of these disorders, we studied one family with DPR and four families with NFJS. We initially reassessed linkage of NFJS/DPR to a previously established locus on 17q11.2-q21. Combined multipoint analysis generated a maximal LOD score of 8.3 at marker D17S800 at a recombination fraction of 0. The disease interval was found to harbor 230 genes, including a large cluster of keratin genes. Heterozygous nonsense or frameshift mutations in KRT14 were found to segregate with the disease trait in all five families. In contrast with KRT14 mutations affecting the central alpha -helical rod domain of keratin 14, which are known to cause epidermolysis bullosa simplex, NFJS/DPR-associated mutations were found in a region of the gene encoding the nonhelical head (E1/V1) domain and are predicted to result in very early termination of translation. These data suggest that KRT14 plays an important role during ontogenesis of dermatoglyphics and sweat glands. Among other functions, the N-terminal part of keratin molecules has been shown to confer protection against proapoptotic signals. Ultrastructural examination of patient skin biopsy specimens provided evidence for increased apoptotic activity in the basal cell layer where KRT14 is expressed, suggesting that apoptosis is an important mechanism in the pathogenesis of NFJS/DPR.

Apoptosis↗
PubMed1997

Conversion of ectoderm into a neural fate by ATH-3, a vertebrate basic helix-loop-helix gene homologous to Drosophila proneural gene atonal.

We have isolated a novel basic helix-loop-helix (bHLH) gene homologous to the Drosophila proneural gene atonal, termed ATH-3, from Xenopus and mouse. ATH-3 is expressed in the developing nervous system, with high levels of expression in the brain, retina and cranial ganglions. Injection of ATH-3 RNA into Xenopus embryos dramatically expands the neural tube and induces ectopic neural tissues in the epidermis but inhibits non-neural development. This ATH-3-induced neural hyperplasia does not require cell division, indicating that surrounding cells which are normally non-neural types adopt a neural fate. In a Xenopus animal cap assay, ATH-3 is able to convert ectodermal cells into neurons expressing anterior markers without inducing mesoderm. Interestingly, a single amino acid change from Ser to Asp in the basic region, which mimics phosphorylation of Ser, severely impairs the anterior marker-inducing ability without affecting general neurogenic activities. These results provide evidence that ATH-3 can directly convert non-neural or undetermined cells into a neural fate, and suggest that the Ser residue in the basic region may be critical for the regulation of ATH-3 activity by phosphorylation.

Amino Acid Sequence↗
PubMed1991

The albino-deletion complex of the mouse: molecular mapping of deletion breakpoints that define regions necessary for development of the embryonic and extraembryonic ectoderm.

Previous complementation analyses with five (c11DSD, c5FR60Hg, c2YPSj, c4FR60Hd, c6H) of the mouse albino deletions defined at least two genes on chromosome 7, known as eed and exed, which are necessary for development of the embryonic and extraembryonic ectoderm, respectively, of early postimplantation embryos. The region of chromosome 7 containing these two genes has now been accessed at the molecular level by cloning two of the deletion breakpoint-fusion fragments. The c2YPSj breakpoints were isolated by cloning an EcoRI fragment containing a copy of an albino region-specific repeat unique to c2YPSj DNA. Similarly, the c11DSD breakpoints were isolated by cloning a c11DSD EcoRI fragment detected by a unique-sequence probe mapping proximal to the albino-coat-color locus. By mapping the cloned breakpoints relative to the remaining three deletions, the c11DSD distal breakpoint was found to define the distal limit of the region containing eed, whereas the c2YPSj and c6H distal breakpoints were found to define the proximal and distal limits, respectively, of the region containing exed.

Albinism↗