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David Schlessinger - One of the best experts on this subject based on the ideXlab platform.
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Lymphotoxin-β regulates periderm differentiation during embryonic skin development
Human Molecular Genetics, 2007Co-Authors: Chang Yi Cui, Makoto Kunisada, Diana Esibizione, Sergei I. Grivennikov, Yulan Piao, Sergei A. Nedospasov, David SchlessingerAbstract:Lymphotoxin-beta (LTbeta) is a key regulator of immune system development, but also affects late stages in hair development. In addition, high expression of LTbeta at an early stage in epidermis hinted at a further function in hair follicle induction or epithelial development. We report that hair follicles were normally induced in LTbeta(-/-) skin, but the periderm detached from the epidermis earlier, accompanied by premature appearance of keratohyalin granules. Expression profiling revealed dramatic down-regulation of a Gene cluster encoding periderm-specific keratin-associated protein 13 and four novel paralogs in LTbeta(-/-) skin prior to periderm detachment. Epidermal differentiation markers, including small proline-rich proteins, filaggrins and several keratins, were also affected, but transiently in LTbeta(-/-) skin at the time of abnormal periderm detachment. As expected, Tabby mice, which lack the EDA Gene, the putative upstream regulator of LTbeta in skin, showed similar though milder periderm histopathology and alterations in Gene expression. Overall, LTbeta shows a primary early function in periderm differentiation, with later transient effects on epidermal and hair follicle differentiation.
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ectodysplasin regulates the lymphotoxin beta pathway for hair differentiation
Proceedings of the National Academy of Sciences of the United States of America, 2006Co-Authors: Chang Yi Cui, Sergei I. Grivennikov, Yulan Piao, Sergei A. Nedospasov, Tsuyoshi Hashimoto, David SchlessingerAbstract:Mutations in the EDA Gene cause anhidrotic/hypohidrotic ectodermal dysplasia, a disorder characterized by defective formation of hair, sweat glands, and teeth in humans and in a mouse model, “Tabby” (Ta). The Gene encodes ectodysplasin, a TNF ligand family member that activates the NF-κB-signaling pathway, but downstream targets and the mechanism of skin appendage formation have been only partially analyzed. Comparative transcription profiling of embryonic skin during hair follicle development in WT and Ta mice identified critical anhidrotic/hypohidrotic ectodermal dysplasia (EDA) effectors in four pathways, three already implicated in follicle formation. They included Shh and its effectors, as well as antagonists for the Wnt (Dkk4) and BMP (Sostdc1) pathways. The fourth pathway was unexpected, a variant NF-κB-signaling cascade based on lymphotoxin-β (LTβ)/RelB. Previously known to participate only in lymphoid organoGenesis, LTβ was enriched in developing hair follicles of WT but not in Ta mice. Furthermore, in mice lacking LTβ, all three types of mouse hair were still formed, but all were structurally abnormal. Guard hairs became wavy and irregular, zigzag/auchen hairs lost their kinks, and in a phenocopy of features of Ta animals, the awl hairs doubled in number and were characteristically distorted and pinched. LTβ-null mice that received WT bone marrow transplants maintained mutant hair phenotypes, consistent with autonomous LTβ action in skin independent of its expression in lymphoid cells. Thus, as an EDA target, LTβ regulates the form of hair in developing hair follicles; and when EDA is defective, failure of LTβ activation can account for part of the Ta phenotype.
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x linked anhidrotic ectodermal dysplasia disruption yields a mouse model for ocular surface disease and resultant blindness
American Journal of Pathology, 2005Co-Authors: Chang Yi Cui, David Schlessinger, Janine A Smith, Chichao ChanAbstract:X-linked anhidrotic/hypohidrotic ectodermal dysplasia (EDA) is caused by mutations in the (EDA) Gene, which is required for the morphoGenesis of ectoderm-derived tissues. Although EDA function in skin appendage development has been studied in EDA mutant “Tabby” mice, we have recently identified characteristic abnormalities in the ocular surface, an ectoderm-derived tissue. Histology of eyes of Tabby males revealed that 1) as previously reported, mice lacked meibomian glands; 2) >80% developed corneal lesions such as neovascularization, keratitis, ulceration, and keratinization identifiable from 9 weeks of age; and 3) > 80% showed ocular surface inflammation (blepharitis and conjunctivitis) when housed in a standard environment. Strikingly, both corneal defects and inflammation were prevented in Tabby mice bearing a transGene for the EDA-A1 isoform, but meibomian glands were restored little if at all. These findings suggest that intact ocular surface health is EDA dependent and that Tabby corneal abnormalities are not solely dependent on meibomian gland lipid secretion. Alternatively, susceptibility to inflammation and other phenotypes could result from failure of the usual EDA receptor to activate nuclear factor-κB transcription factors. This can be further tested in Tabby and Tabby-EDA transgenic mice, which provide unique models of severe ocular surface disease.
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inducible mEDA a1 transGene mediates sebaceous gland hyperplasia and differential formation of two types of mouse hair follicles
Human Molecular Genetics, 2003Co-Authors: Meredith C Durmowicz, Anand K. Srivastava, Chris Ottolenghi, Tsuyoshi Hashimoto, Bradley L Griggs, David SchlessingerAbstract:EDA splice isoforms EDA-A1 and EDA-A2 belong to the TNF ligand family and regulate skin appendage formation by activating NF-kB- and JNK- promoted transcription. To analyze their action further, we conditionally expressed the isoforms as tetracycline (‘Tet’)-regulated transGenes in Tabby (EDA-negative) and wild-type mice. Expression of only the mEDA-A1 transGene had two types of effects during embryoGenesis: (1) determinative effects on sweat glands and hair follicles. In Tabby mice, one type of hair follicle (‘guard hair’) was restored, whereas a second type, the dominant undercoat hair follicle (‘zigzag’) was not; furthermore, the transGene sharply suppressed zigzag hair formation in wild-type mice, with the overall numbers of back hair follicles remaining the same; and (2) trophic effects on sebaceous and Meibomian glands. Marked hyperplasia resulted from expansion of the sebocyte-producing zone in sebaceous glands, with particularly high expression of the transGene and the replication marker PCNA, and correspondingly high production of sebum. The phenotypic effects of mEDA-A1 on sebaceous glands, but not on hair follicles, were reversed when the Gene was repressed in adult animals. The results thus reveal both initiating and trophic isoform-specific effects of the EDA Gene, and suggest a possible balance of isoform interactions in skin appendage formation.
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EDA targets revealed by skin Gene expression profiles of wild type tabby and tabby EDA a1 transgenic mice
Human Molecular Genetics, 2002Co-Authors: Chang Yi Cui, Ken Hashimoto, David Schlessinger, Anand K. Srivastava, Andrew J. Hartung, Meredith C Durmowicz, Tetsuya S Tanaka, Tadashi TezukaAbstract:Mutations in the EDA Gene cause anhidrotic ectodermal dysplasia (EDA), with lesions in skin appendage formation. To begin to analyze EDA pathways, we have used expression profiling on 15,000-Gene mouse cDNA microarrays, comparing adult mouse skin from wild-type, EDA-defective (Tabby) mice, and Tabby mice supplemented with the EDA-A1 isoform, which is sufficient to rescue multiple Tabby phenotypes. Given the sensitivity of the current microarray system, 8500 Genes (60%) were estimated to be expressed, including transcription factors and growth-regulatory Genes that had not previously been identified in skin; but only 24 (0.16%), one-third of them novel, showed significant differences between wild type and Tabby. An additional eight Genes not included in the 15,000 Gene set were shown to have expression differences by real-time RT-PCR. Sixteen of 32 affected Genes were restored significantly toward wild-type levels in EDA-A1 transgenic Tabby mice. Significant up-regulation in Tabby skin was observed for several dermal matrix Genes, including Col1a1, Col1a2, Col3a1 and SPARC: In contrast, down-regulation occurred for the NEMO/NF-kappa B pathway, already implicated in skin appendage formation, and even more markedly for a second pathway, JNK/c-jun/c-fos and their target Genes, that has not previously been clearly associated with skin development. These data are consistent with the regulation of the NF-kappa B pathway by EDA, and support its involvement in the regulation of the JNK pathway as well.
Juha Merilä - One of the best experts on this subject based on the ideXlab platform.
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identifying footprints of directional and balancing selection in marine and freshwater three spined stickleback gasterosteus aculeatus populations
Molecular Ecology, 2008Co-Authors: Hannu Mäkinen, J M Cano, Juha MeriläAbstract:Natural selection is expected to leave an imprint on the neutral polymorphisms at the adjacent genomic regions of a selected Gene. While directional selection tends to reduce within-population Genetic diversity and increase among-population differentiation, the reverse is expected under balancing selection. To identify targets of natural selection in the three-spined stickleback (Gasterosteus aculeatus) genome, 103 microsatellite and two indel markers including expressed sequence tags (EST) and quantitative trait loci (QTL)-associated loci, were genotyped in four freshwater and three marine populations. The results indicated that a high proportion of loci (14.7%) might be affected by balancing selection and a lower proportion (2.8%) by directional selection. The strongest signatures of directional selection were detected in a microsatellite locus and two indel markers located in the intronic regions of the EDA-Gene coding for the number of lateral plates. Yet, other microsatellite loci previously found to be informative in QTL-mapping studies revealed no signatures of selection. Two novel microsatellite loci (Stn12 and Stn90) located in chromosomes I and VIII, respectively, showed signals of directional selection and might be linked to genomic regions containing Gene(s) important for adaptive divergence. Although the coverage of the total genomic content was relatively low, the predominance of balancing selection signals is in agreement with the contention that balancing, rather than directional selection is the predominant mode of selection in the wild.
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identifying footprints of directional and balancing selection in marine and freshwater three spined stickleback gasterosteus aculeatus populations
Molecular Ecology, 2008Co-Authors: Hannu Mäkinen, J M Cano, Juha MeriläAbstract:: Natural selection is expected to leave an imprint on the neutral polymorphisms at the adjacent genomic regions of a selected Gene. While directional selection tends to reduce within-population Genetic diversity and increase among-population differentiation, the reverse is expected under balancing selection. To identify targets of natural selection in the three-spined stickleback (Gasterosteus aculeatus) genome, 103 microsatellite and two indel markers including expressed sequence tags (EST) and quantitative trait loci (QTL)-associated loci, were genotyped in four freshwater and three marine populations. The results indicated that a high proportion of loci (14.7%) might be affected by balancing selection and a lower proportion (2.8%) by directional selection. The strongest signatures of directional selection were detected in a microsatellite locus and two indel markers located in the intronic regions of the EDA-Gene coding for the number of lateral plates. Yet, other microsatellite loci previously found to be informative in QTL-mapping studies revealed no signatures of selection. Two novel microsatellite loci (Stn12 and Stn90) located in chromosomes I and VIII, respectively, showed signals of directional selection and might be linked to genomic regions containing Gene(s) important for adaptive divergence. Although the coverage of the total genomic content was relatively low, the predominance of balancing selection signals is in agreement with the contention that balancing, rather than directional selection is the predominant mode of selection in the wild.
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The utility of QTL-Linked markers to detect selective sweeps in natural populations--a case study of the EDA Gene and a linked marker in threespine stickleback.
Molecular Ecology, 2006Co-Authors: Jose M. Cano, Chikako Matsuba, Hannu Mäkinen, Juha MeriläAbstract:Sequence polymorphisms in coding Genes and variability in quantitative trait loci (QTL)linked markers can be used to uncover the evolutionary mechanisms of traits involved in adaptive processes. We studied sequence variation in the EDA Gene and allelic variation in 18 microsatellites — one of which (Gac4174) is linked with the EDA QTL — in low, partially and completely plated morphs from eight threespine stickleback European populations. The results agree with previous studies in that EDA polymorphism is closely related to plate number variation: EDA sequences grouped populations into low and completely plated morphs, whereas microsatellites failed to do so. Furthermore, partially plated fish were heterozygous with respect to the distinctive EDA alleles for completely and low plated morphs, indicating that completely plated morph alleles are not entirely dominant in controlling the expression of lateral plate number. An examination of population differentiation in plate number with quantitative Genetic methods revealed that the degree of differentiation exceeded that expected from Genetic drift alone ( Q ST > F ST ). Our results support the adaptive Genetic differentiation of plate morphs and the view that distinctive EDA Gene polymorphism occurs in similar sites across the distribution range of this species. Yet, allele frequency differentiation in the Gac4174 microsatellite locus, informative in experimental crosses for plate number variation, did not differ from that of neutral markers and, was therefore unable to detect the signature of natural selection responsible for population divergence.
Wasim Ahmad - One of the best experts on this subject based on the ideXlab platform.
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A novel missense mutation in the ectodysplasin-A (EDA) Gene underlies X-linked recessive nonsyndromic hypodontia.
International Journal of Dermatology, 2010Co-Authors: Muhammad Ayub, Fazal Ur-rehman, Masoom Yasinzai, Wasim AhmadAbstract:Background Nonsyndromic hypodontia or congential absence of one or more permanent teeth is a common anomaly of dental development in humans. This condition may be inherited in an autosomal (dominant/recessive) or X-linked (dominant/recessive) mode. Mutations in three Genes, PAX9, MSX1, and AXIN2, have been determined to be associated with autosomal dominant and recessive tooth aGenesis. Recent studies in a few families showed that mutations in the ectodysplasin A (EDA) Gene result in X-linked nonsyndromic hypodontia. Methods Genotyping of a five-Generation Pakistani family with X-linked isolated hypodontia having three affected men was carried out using EDA-linked polymorphic microsatellite markers on chromosome Xq12-q13.1. To screen for a mutation in the EDA Gene, all of its coding exons and splice junction sites were PCR amplified from genomic DNA of affected and unaffected individuals of the family and sequenced directly in an ABI Prism 310 automated DNA sequencer. Results We successfully mapped the affected locus to chromosome Xq12-q13.1, and found a novel missense mutation (c.993G>C) in the EDA Gene in the affected men. The mutation causes substitution of glutamine with histidine (p.Q331H) in the tumor necrosis factor homology domain of EDA. Conclusions A mutation identified in this study extends the body of evidence implicating the EDA Gene in X-linked nonsyndromic hypodontia and supports the role of EDA-EDAR-EDARADD signaling in the morphoGenesis of teeth.
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Recurrent mutations in functionally-related EDA and EDAR Genes underlie X-linked isolated hypodontia and autosomal recessive hypohidrotic ectodermal dysplasia
Archives of Dermatological Research, 2009Co-Authors: Zahid Azeem, Muhammad Tariq, Syed Kamran-ul-hassan Naqvi, Muhammad Ansar, Abdul Wali, Abdul Khaliq Naveed, Ghazanfar Ali, Muhammad Jawad Hassan, Sulman Basit, Wasim AhmadAbstract:Mutations in three functionally related Genes EDA , EDAR and EDARDD have been reported to cause hypohidrotic ectodermal dysplasia (HED), which is characterized by sparse hair, reduced ability to sweat, and hypodontia. In few cases mutations in the EDA Gene have been found to result in X-linked recessive isolated hypodontia. In the study, presented here, we have ascertained two large Pakistani families (A and B) with autosomal recessive form of hypohidrotic ectodermal dysplasia and X-linked recessive isolated hypodontia. Genetic mapping showed linkage of family A to EDAR Gene on chromosome 2q11-q13 and family B to EDA Gene on chromosome Xq12-q13.1. Subsequently, DNA sequencing of the coding regions of EDAR and EDA Genes revealed previously described mutations. Sequence analysis identified a four base-pair splice-junction deletion mutation (c.718_721delAAAG) in EDAR Gene in family A and a missense mutation (c.T1091C; p.M364T) in EDA Gene in family B. Recurrence of mutations in EDAR and EDA Genes in unrelated families is evocative of the dispersion of ancestral chromosome in different locality groups through common ancestors.
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novel mutations in the EDAr Gene in two pakistani consanguineous families with autosomal recessive hypohidrotic ectodermal dysplasia
British Journal of Dermatology, 2005Co-Authors: Muhammad Naeem, Dost Muhammad, Wasim AhmadAbstract:Summary Background Hypohidrotic ectodermal dysplasia (HED) is a human heritable disorder characterized by sparse hair, a lack of sweat glands and malformation of teeth. There are X-linked, autosomal recessive and autosomal dominant forms of this disorder. Mutations in the EDA Gene cause X-linked HED and mutations in either the EDAR or the EDARADD Genes cause autosomal forms of HED. Objectives To identify pathogenic mutations in two consanguineous Pakistani families (A and B) with 11 affected individuals demonstrating the autosomal recessive form of HED. Methods Genotyping of 17 members of the two families, including eight affected and nine unaffected individuals, was carried out by using polymorphic markers D2S293, D2S1893 and D2S1891, which are closely linked to the EDAR Gene on chromosome 2q11-q13. To screen for mutations in the EDAR Gene, all of its exons and splice junctions were polymerase chain reaction amplified from genomic DNA and sequenced directly in an ABI Prism 310 automated sequencer. Results Genotyping results showed linkage in both the Pakistani families to the EDAR locus. Sequence analysis of the EDAR Gene identified two novel mutations in the families: a missense mutation (G382S) in family A and a 4-bp deletion (718delAAAG) in family B. Conclusions We describe novel mutations in the EDAR Gene in two Pakistani families affected with the autosomal recessive form of HED. Our findings extend the body of evidence that supports the importance of the ectodysplasin A1 isoform receptor, a member of the tumour necrosis factor receptor family, in the development of ectodermal appendages.
Zhuan Bian - One of the best experts on this subject based on the ideXlab platform.
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Mutation detection and prenatal diagnosis of XLHED pedigree.
PeerJ, 2017Co-Authors: Yao Lin, Wei Yin, Zhuan BianAbstract:Background The phenotypic characters of X -linked Hypohidrotic Ectodermal Dysplasia (XLHED) are the dysplasia of epithelial- and mesenchymal-derived organs. Ectodysplasin (EDA) is the causative Gene of XLHED. Methods The current study reported a large Chinese XLHED pedigree. The genomic DNA of adult and fetus was extracted from peripheral blood and shed chorion cell respectively. The nucleotide variation in EDA Gene was screened through direct sequencing the coding sequence. The methylation state of EDA Gene's promoter was evaluated by pyrosequencing. Results This Chinese XLHED family had two male patients and three carriers. All of them were with a novel EDA frameshift mutation. The mutation, c.172-173insGG, which leads to an immediate premature stop codon in exon one caused severe structural changes of EDA. Prenatal diagnosis suggested that the fetus was a female carrier. The follow-up observation of this child indicated that she had mild hypodontia of deciduous teeth at age six. The methylation level of EDA Gene's promoter was not related to carriers' phenotype changes in this family. Discussion We reported a new frameshift mutation of EDA Gene in a Chinese family. Prenatal diagnosis can help to predict the disease status of the fetus.
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Methylation State of the EDA Gene Promoter in Chinese X-Linked Hypohidrotic Ectodermal Dysplasia Carriers
2016Co-Authors: Wei Yin, Hua-li Fan, Zhuan BianAbstract:Introduction: Hypodontia, hypohidrosis, sparse hair and characteristic faces are the main characters of X-linked hypohidrotic ectodermal dysplasia (XLHED) which is caused by Genetic ectodysplasin A (EDA) deficiency. Heterozygous female carriers tend to have mild to moderate XLHED phenotype, even though 30 % of them present no obvious symptom. Methods: A large Chinese XLHED family was reported and the entire coding region and exon–intron boundaries of EDA Gene were sequenced. To elucidate the mechanism for carriers ’ tempered phenotype, we analyzed the methylation level o
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Methylation state of the EDA Gene promoter in Chinese X-linked hypohidrotic ectodermal dysplasia carriers.
PLoS ONE, 2013Co-Authors: Wei Yin, Hua-li Fan, Zhuan BianAbstract:Introduction Hypodontia, hypohidrosis, sparse hair and characteristic faces are the main characters of X-linked hypohidrotic ectodermal dysplasia (XLHED) which is caused by Genetic ectodysplasin A (EDA) deficiency. Heterozygous female carriers tend to have mild to moderate XLHED phenotype, even though 30% of them present no obvious symptom.
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Mutations in the EDA Gene are responsible for X-linked hypohidrotic ectodermal dysplasia and hypodontia in Chinese kindreds.
European Journal of Oral Sciences, 2008Co-Authors: Hua-li Fan, Wei Yin, Lisong Shi, Bo Hua, Guangtai Song, Bin Shi, Zhuan BianAbstract:X-linked hypohidrotic ectodermal dysplasia (XLHED, OMIM 305100) is a rare congenital disorder that results in the defective development of teeth, hair, nails, and eccrine sweat glands. Previous studies found that mutations in the ectodysplasin A (EDA) Gene are associated with XLHED. In the present study, we investigated four Chinese families suffering from classical XLHED and investigated two additional families segregating hypodontia in an X-linked recessive manner. Mutations were characterized respectively in the EDA Gene in all families, and five of these mutations were found to be novel. Among these mutations, five were missense (c.200A>T, c.463C>T, c.758T>C, c.926T>G, and c.491A>C) and located in the functional domain of EDA, and one was a splice donor site mutation in intron 5 (c.IVS5 + 1G>A), which may result in an alternative transcript derived from a new cryptic splice site. Our data further confirm that EDA mutations could cause both XLHED and isolated hypodontia and provide evidence that EDA is a strong candidate Gene for tooth Genesis.
Juha Kere - One of the best experts on this subject based on the ideXlab platform.
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ectodysplasin is a collagenous trimeric type ii membrane protein with a tumor necrosis factor like domain and co localizes with cytoskeletal structures at lateral and apical surfaces of cells
Human Molecular Genetics, 1999Co-Authors: Sini Ezer, David Schlessinger, Mònica Bayés, Juha KereAbstract:Anhidrotic ectodermal dysplasia (EDA) is a human Genetic disorder of impaired ectodermal appendage development. The EDA Gene encodes isoforms of a novel transmembrane protein, ectodysplasin. The sequence of the longest isoform includes an interrupted collagenous domain of 19 Gly-X-Y repeats and a motif conserved in the tumor necrosis factor (TNF)-related ligand family. In order to understand better the function of the ectodysplasin protein molecule and its domains, we have studied the processing and localization of wild-type and mutated isoforms in transfected human fetal kidney 293 and monkey kidney COS-1 cells. Similar to other members of collagenous membrane proteins and members of TNF-related ligands, ectodysplasin is a type II membrane protein and it forms trimers. The membrane localization of ectodysplasin is asymmetrical: it is found on the apical and lateral surfaces of the cells where it co-localizes with cytoskeletal structures. The TNF-like motif and cysteines found near the C-terminus are necessary for correct transport to the cell membrane, but the intracellular and collagenous domains are not required for the localization pattern. Our results suggest that ectodysplasin is a new member in the TNF-related ligand family involved in the early epithelial-mesenchymal interaction that regulates ectodermal appendage formation.
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The Anhidrotic Ectodermal Dysplasia Gene (EDA) Undergoes Alternative Splicing and Encodes Ectodysplasin-A with Deletion Mutations in Collagenous Repeats
Human Molecular Genetics, 1998Co-Authors: Mònica Bayés, Johanna Pispa, Irma Thesleff, Anand K. Srivastava, Andrew J. Hartung, Sini Ezer, Juha KereAbstract:Anhidrotic ectodermal dysplasia (EDA) is an X-linked recessive disorder which affects ectodermal structures. A cDNA encoding a 135 amino acid protein with mutations in 5-10% of EDA patients has been reported. We have built up a complete splicing map of the EDA Gene and characterized the longest and what most probably represents the full-length EDA transcript, EDA-A. It encodes a 391 amino acid transmembrane protein with a short collagenous domain, (Gly-X-Y) 19 , and is highly homologous to the protein mutated in Tabby mice (Ta-A). Four new transcripts that code for truncated proteins lacking the collagenous domain were also detected. The splice variants show different expression patterns in eight tissues analyzed, suggesting a regulatory mechanism for Gene expression. The EDA-A form of the protein is transported to the cell membrane and induces rounding of the cells, properties also associated with the 135 amino acid isoform. We have determined the genomic organization and the exon-intron boundaries of the EDA Gene. SSCP analysis of the nine exons corresponding to EDA-A allowed the identification of mutations in 12 out of 15 EDA patients. Interestingly, three mutations removed either two or four of the Gly-X-Y repeats without interrupting the reading frame, thus suggesting a functional role for the collagenous domain. Our results will allow mutation diagnostics in the majority of patients.
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the Gene defective in anhidrotic ectodermal dysplasia is expressed in the developing epithelium neuroectoderm thymus and bone
Journal of Histochemistry and Cytochemistry, 1998Co-Authors: O. Montonen, David Schlessinger, Sini Ezer, Anand Srivastava, Ulpu Saarialhokere, Riitta Herva, Marjaliisa Karjalainenlindsberg, Ilkka Kaitila, Juha KereAbstract:Anhidrotic ectodermal dysplasia (EDA) is characterized by defects in the development of teeth, hair, and sweat glands. To study the expression of the human Gene defective in EDA in human fetal development (Weeks 6–23 of gestational age) and in adult tissues, in situ hybridization and immunohistochemistry were used. First signs of expression were detected at Week 8 in epidermis and in neuroectodermal cells. Starting at Week 12, osteoblasts and thymus were positive for EDA mRNA. Hair follicles expressed EDA mRNA from 18 weeks. The presence of the EDA protein coincided with mRNA expression in the tissues examined. The expression pattern of the EDA Gene is consistent with typical involvement of the skin in the syndrome. However, the expression is not limited to the ectodermal tissues and many sites of expression are not obviously reflected in the clinical features of the syndrome.
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fine mapping of the EDA Gene a translocation breakpoint is associated with a cpg island that is transcribed
American Journal of Human Genetics, 1996Co-Authors: Anand Srivastava, David Schlessinger, O. Montonen, J. Limon, E. Chen, Primo Baybayan, Ulpu Saarialhokere, Juha KereAbstract:In order to identify the Gene for human X-linked anhidrotic ectodermal dysplasia (EDA), a translocation breakpoint in a female with t(X;1)(q13.1;p36.3) and EDA (patient AK) was finely mapped. The EDA region contains five groups of rare-cutter restriction sites that define CpG islands. The two more centromeric of these islands are associated with transcripts of 3.5 kb and 1.8 kb. The third CpG island maps within <1 kb of the translocation breakpoint in patient AK, as indicated by a genomic rearrangement, and approximately 100 kb centromeric from another previously mapped translocation breakpoint (patient AnLy). Northern analysis with a probe from this CpG island detected an approximately 6-kb mRNA in several fetal tissues tested. An extended YAC contig of 1,200 kb with an average of fivefold coverage was constructed. The two most telomeric CpG islands map 350 kb telomeric of the two translocations. Taken together, the results suggest that the CpG island just proximal of the AK translocation breakpoint lies at the 5' end of a candidate Gene for EDA.
