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Tania Attie-bitach - One of the best experts on this subject based on the ideXlab platform.
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Autosomal recessive IFT57 hypomorphic mutation cause ciliary transport defect in unclassified oral-facial-digital Syndrome with short stature and brachymesophalangia
Clinical Genetics, 2016Co-Authors: Julien Thevenon, Laurence Duplomb Jego, A. Saunier, M. Avila, Virginie Carmignac, Ange-line Bruel, Judith Saint-onge, Yannis Duffourd, B. Franco, Tania Attie-bitachAbstract:The 13 subtypes of oral-facial-digital Syndrome (OFDS) belong to the heterogeneous group of ciliopathies. Disease-causing genes encode for centrosomal proteins, components of the transition zone or proteins implicated in ciliary signaling. A unique consanguineous family presenting with an unclassified OFDS with skeletal dysplasia and brachymesophalangia was explored. Homozygosity mapping and exome sequencing led to the identification of a homozygous mutation in IFT57, which encodes a protein implicated in ciliary transport. The mutation caused splicing anomalies with reduced expression of the wild-type transcript and protein. Both anterograde ciliary transport and sonic hedgehog signaling were significantly decreased in subjects' fibroblasts compared with controls. Sanger sequencing of IFT57 in 13 OFDS subjects and 12 subjects with Ellis-Van Creveld Syndrome was negative. This report identifies the implication of IFT57 in human pathology and highlights the first description of a ciliary transport defect in OFDS, extending the genetic heterogeneity of this subgroup of ciliopathies.
Victor L Ruizperez - One of the best experts on this subject based on the ideXlab platform.
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ellis van Creveld Syndrome and weyers acrodental dysostosis are caused by cilia mediated diminished response to hedgehog ligands
American Journal of Medical Genetics Part C-seminars in Medical Genetics, 2009Co-Authors: Victor L Ruizperez, Judith A GoodshipAbstract:Ellis-Van Creveld Syndrome (EvC; OMIM 225500) is a recessive disorder comprising chondrodysplasia, polydactyly, nail dysplasia, orofacial abnormalities and, in a proportion of patients, cardiovascular malformations. Weyers acrodental dysostosis (Weyers; OMIM 193530) is an allelic dominant disorder comprising polydactyly, nail dysplasia, and orofacial abnormalities. EvC results from loss-of-function mutations in EVC or EVC2, the phenotype associated with the mutations in these two genes being indistinguishable. Three convincing causative mutations have been identified in patients with Weyers acrodental dysostosis, which are clustered in the last coding exon of EVC2 and lead to production of a truncated protein lacking the final 43 amino acids. Localization and function of EVC and EVC2 are inferred from studying the murine orthologs. Both Evc and Evc2 proteins localize to the basal bodies of primary cilia and analysis of an Ellis-Van Creveld mouse model, which includes the limb shortening and tooth abnormalities of EvC patients, has demonstrated Hedgehog signaling defects in the absence of Evc. The loss of Evc2 has not been studied directly, but Hedgehog signaling is impaired when a mutant murine Evc2 Weyer variant is expressed in vitro. We conclude that the phenotypic abnormalities in EvC and Weyers Syndrome result from tissue specific disruption of the response to Hh ligands.
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mutations in a new gene in ellis van Creveld Syndrome and weyers acrodental dysostosis
Nature Genetics, 2000Co-Authors: Victor L Ruizperez, Susan E Ide, Tim M Strom, Bettina Lorenz, David I Wilson, Kathryn Woods, Lynn Mertens King, Clair A Francomano, Peter FreisingerAbstract:Ellis-Van Creveld Syndrome (EvC, MIM 225500) is an autosomal recessive skeletal dysplasia characterized by short limbs, short ribs, postaxial polydactyly and dysplastic nails and teeth. Congenital cardiac defects, most commonly a defect of primary atrial septation producing a common atrium, occur in 60% of affected individuals. The disease was mapped to chromosome 4p16 in nine Amish subpedigrees and single pedigrees from Mexico, Ecuador and Brazil. Weyers acrodental dysostosis (MIM 193530), an autosomal dominant disorder with a similar but milder phenotype, has been mapped in a single pedigree to an area including the EvC critical region. We have identified a new gene (EVC), encoding a 992-amino-acid protein, that is mutated in individuals with EvC. We identified a splice-donor change in an Amish pedigree and six truncating mutations and a single amino acid deletion in seven pedigrees. The heterozygous carriers of these mutations did not manifest features of EvC. We found two heterozygous missense mutations associated with a phenotype, one in a man with Weyers acrodental dysostosis and another in a father and his daughter, who both have the heart defect characteristic of EvC and polydactyly, but not short stature. We suggest that EvC and Weyers acrodental dysostosis are allelic conditions.
De Moraes Márcio - One of the best experts on this subject based on the ideXlab platform.
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Presença de Dente Neo-Natal em Portador da Síndrome de Ellis Van-Creveld: Relato de Caso
Sociedade Portuguesa de Estomatologia e Medicina Dentária. Published by Elsevier España S.L., 2010Co-Authors: Farah, Gustavo Jacobucci, Ferreira, Gustavo Zanna, Serra Silva, Fabrício E M., De Moraes MárcioAbstract:AbstractThe aim of this article is go over the literature and describe a case of Ellis Van Creveld Syndrome, in which the patient presented a neo-natal tooth Just-born and premature patient, female, came to the hospital of Limeira, São Paulo, and was attended by the Surgery and Maxillofacial Traumatology group from the Dentistry College of Piracicaba (FOPUNICAMP). Her main complaint was the neo-natal tooth. During the extraoral examination it was detected a tower shaped cranium, shortened limbs, lank and sparse hair, bilateral postaxial polydactyly, hypoplasic nails and heart changes. In the intraoral examination the signs included multiple labial frenum associated with gingival changes, and presence of a conic neo natal teeth. The diagnosis of Ellis van Creveld Syndrome was based on the clinical and radiographic findings that included characteristics from Chondroectodermal dysplasia. It was not found any history of this Syndrome in her family. Being thus, the Ellis Van Creveld Syndrome although rare, presents many characteristics that demand a multidiscipline treatment. Odontologic manifestations are there, that's why surgeons, especially dentists, must be aware of it so that their behavior can contribute for the patient well-being.ResumoO objectivo deste artigo é revisar a literatura e relatar um caso de Síndrome de Ellis-Van Creveld, no qual o paciente apresenta um dente neo-natal. Paciente recém-nascido e prematuro, género feminino, foi atendido no hospital da cidade de Limeira-SP, pela equipe de Cirurgia e Traumatologia Buco-maxilo-facial da Faculdade de Odontologia de Piracicaba (FOP-UNICAMP), com queixa de dente neo-natal. Ao exame físico extra-bucal apresentava crânio em forma de torre, membros encurtados, cabelos finos e esparsos, polidactilia pós-axial bilateral, unhas hipoplásicas e alterações cardíacas. Ao exame físico intra-bucal os sinais de anomalia incluíam múltiplos freios labiais associados a alterações gengivais, e presença de denta neo-natal com formato cónico. O diagnóstico de síndrome de Ellis-Van Creveld foi baseado nos achados clínicos e radiográficos que incluíam características da displasia condroectodérmica. Entretanto, não foi encontrada história familiar de manifestação desta síndrome. Sendo assim, a Síndrome de Ellis-Van Creveld apesar de rara apresenta várias características que exigem tratamento multidisciplinar. Como as manifestações odontológicas estão presentes, o médico dentista deve estar atento para que sua conduta possa contribuir para o acompanhamento e bem-estar do paciente
Julien Thevenon - One of the best experts on this subject based on the ideXlab platform.
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Autosomal recessive IFT57 hypomorphic mutation cause ciliary transport defect in unclassified oral-facial-digital Syndrome with short stature and brachymesophalangia
Clinical Genetics, 2016Co-Authors: Julien Thevenon, Laurence Duplomb Jego, A. Saunier, M. Avila, Virginie Carmignac, Ange-line Bruel, Judith Saint-onge, Yannis Duffourd, B. Franco, Tania Attie-bitachAbstract:The 13 subtypes of oral-facial-digital Syndrome (OFDS) belong to the heterogeneous group of ciliopathies. Disease-causing genes encode for centrosomal proteins, components of the transition zone or proteins implicated in ciliary signaling. A unique consanguineous family presenting with an unclassified OFDS with skeletal dysplasia and brachymesophalangia was explored. Homozygosity mapping and exome sequencing led to the identification of a homozygous mutation in IFT57, which encodes a protein implicated in ciliary transport. The mutation caused splicing anomalies with reduced expression of the wild-type transcript and protein. Both anterograde ciliary transport and sonic hedgehog signaling were significantly decreased in subjects' fibroblasts compared with controls. Sanger sequencing of IFT57 in 13 OFDS subjects and 12 subjects with Ellis-Van Creveld Syndrome was negative. This report identifies the implication of IFT57 in human pathology and highlights the first description of a ciliary transport defect in OFDS, extending the genetic heterogeneity of this subgroup of ciliopathies.
Ruiz-pérez, Victor L. - One of the best experts on this subject based on the ideXlab platform.
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Phenotypic variation in patients with homozygous c.1678G>T mutation in EVC gene: Report of two mexican families with Ellis-Van Creveld Syndrome
'International Scientific Information Inc.', 2017Co-Authors: Ibarra-ramirez Marisol, Campos-acevedo, Luis Daniel, Lugo-trampe Jose, Martínez-garza, Laura E., Martinez-glez Víctor, Valencia María, Lapunzina Pablo, Ruiz-pérez, Victor L.Abstract:[Background]: Ellis-Van Creveld Syndrome is an autosomal recessive chondro-ectodermal dysplasia characterized by disproportionate short stature, limb shortening, narrow chest, postaxial polydactyly and dysplastic nails and teeth. In addition, 60% of cases present congenital heart defects. Ellis-Van Creveld Syndrome is predominantly caused by mutations in the EVC or EVC2 (4p16) genes, with only a few cases caused by mutations in WDR35.[Case Report]: Here, we report on two Mexican families with patients diagnosed with Ellis-Van Creveld Syndrome. Family 1 includes four patients: three females of 15, 18, and 23 years of age and a 7-year old male. Family 2 has only one affected newborn male. All patients exhibited multiple features including hypodontia, dysplastic teeth, extra frenula, mild short stature, distal limb shortening, postaxial polydactyly of hands and feet, nail dystrophy, and knee joint abnormalities. Only two patients had an atrial septal defect. In all cases, molecular analysis by Sanger sequencing identified the same homozygous mutation in exon 12 of EVC, c.1678G>T, which leads to a premature stop codon.[Conclusions]: The mutation c.1678G>T has been previously reported in another Mexican patient and it appears to be a recurrent mutation in Mexico which could represent a founder mutation. The large number of patients in this case allows the clinical variability and spectrum of manifestations present in individuals with Ellis-Van Creveld Syndrome even if they carry the same homozygous mutation in a same family.Peer reviewe
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Ellis van Creveld Syndrome in a Tunisian child revealed by an Eisenmenger Syndrome
King Faisal Specialist Hospital & Research Centre (General Organization) Saudi Arabia. Production and hosting by Elsevier B.V., 2015Co-Authors: Ajmi Houda, Ruiz-pérez, Victor L., Hassayoun Saida, Mabrouk Sameh, Mahdoui Sana, Boughzela Essia, Zouari Noura, Abroug SaoussanAbstract:AbstractEllis-Van Creveld Syndrome (EvC) is an autosomal recessive inherited disease resulting from mutations in EVC1 or EVC2. Patients with this condition normally have chondrodysplasia, postaxial polydactyly, ectodermal dysplasia and congenital heart defects. We report the case of a 13-year-old Tunisian child who was admitted for cyanosis and acute heart failure. On clinical examination, he presented with typical features of EvC, cyanosis and dyspnea. EvC was confirmed by genetic tests, and echocardiography showed a partial atrioventricular canal defect with supra-systemic pulmonary artery pressure. The patient was treated; however, the evolution was fatal
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Specific variants in WDR35 cause a distinctive form of Ellis-Van Creveld Syndrome by disrupting the recruitment of the EvC complex and SMO into the cilium
'Oxford University Press (OUP)', 2015Co-Authors: Caparrós-martín, José A., Valencia María, Nevado Julian, Goodship, Judith A., Aglan Mona, Temtamy Samia, Vázquez Laura, Ruiz-pérez, Victor L.Abstract:et al.Most patients with Ellis-Van Creveld Syndrome (EvC) are identified with pathogenic changes in EVC or EVC2, however further genetic heterogeneity has been suggested. In this report we describe pathogenic splicing variants in WDR35, encoding retrograde intraflagellar transport protein 121 (IFT121), in three families with a clinical diagnosis of EvC but having a distinctive phenotype. To understand why WDR35 variants result in EvC, we analysed EVC, EVC2 and Smoothened (SMO) in IFT-A deficient cells. We found that the three proteins failed to localize to Wdr35−/− cilia, but not to the cilium of the IFT retrograde motor mutant Dync2h1−/−, indicating that IFT121 is specifically required for their entry into the ciliary compartment. Furthermore expression of Wdr35 disease cDNAs in Wdr35−/− fibroblasts revealed that the newly identified variants lead to Hedgehog signalling defects resembling those of Evc−/− and Evc2−/− mutants. Together our data indicate that splicing variants in WDR35, and possibly in other IFT-A components, underlie a number of EvC cases by disrupting targeting of both the EvC complex and SMO to cilia.This work was supported by the Spanish Ministry of Economy and Competitiveness (SAF2013-43365-R) and by funding from the Italian Ministry of Health (RF-2010-2310935, RC-2014 to A.D.L.).Peer Reviewe
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Ellis-Van Creveld Syndrome and Weyers acrodental dysostosis are caused by cilia-mediated diminished response to Hedgehog ligands
'Wiley', 2013Co-Authors: Ruiz-pérez, Victor L., Goodship, Judith A.Abstract:Ellis-Van Creveld Syndrome (EvC; OMIM 225500) is a recessive disorder comprising chondrodysplasia, polydactyly, nail dysplasia, orofacial abnormalities and, in a proportion of patients, cardiovascular malformations. Weyers acrodental dysostosis (Weyers;OMIM 193530) is an allelic dominant disorder comprising polydactyly, nail dysplasia, and orofacial abnormalities. EvC results from loss-of-function mutations in EVC or EVC2, the phenotype associated with the mutations in these two genes being indistinguishable. Three convincing causative mutations have been identified in patients with Weyers acrodental dysostosis, which are clustered in the last coding exon of EVC2 and lead to production of a truncated protein lacking the final 43 amino acids. Localization and function of EVC and EVC2 are inferred from studying the murine orthologs. Both Evc and Evc2 proteins localize to the basal bodies of primary cilia and analysis of an Ellis-Van Creveld mouse model, which includes the limb shortening and tooth abnormalities of EvC patients, has demonstrated Hedgehog signaling defects in the absence of Evc. The loss of Evc2 has not been studied directly, but Hedgehog signaling is impaired when a mutant murine Evc2 Weyer variant is expressed in vitro. We conclude that the phenotypic abnormalities in EvC and Weyers Syndrome result from tissue specific disruption of the response to Hh ligands. © 2009 Wiley-Liss, Inc.Funded by: Spanish Ministry of Science and Innovation. Grant Number: SAF-62291; Ramon Areces Foundation and European Union. Grant Number: LSHM-CT-2007-03741.Peer Reviewe
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Ellis-Van Creveld Syndrome in a fetus with rhizomelia and polydactyly. Report of a case diagnosed by genetic analysis, and correlation with pathological andradiologic findings
'Elsevier BV', 2013Co-Authors: Peraita-ezcurra Milena, Ruiz-pérez, Victor L., Trujillo-tiebas, María JoséAbstract:Ellis-Van Creveld Syndrome is an autosomal recessive disorder mainly characterized by a disproportionate limb dwarfism, chondroectodermal dysplasia, congenital heart disease, postaxial polydactyly, and dysplastic fingernails and teeth. Only 300 cases have been published worldwide. We report a 21-week fetus with rhizomelia and polydactyly detected. Gross photographs, radiologic studies and pathological study were performed leading to the clinico-pathological suspicion of EvC. DNA from fresh fetal tissue was extracted for sequencing the EVC and EVC2 genes. p.W215X and p.R677X mutations were identified in the EVC2 gene in the fetal sample. Parental sample analysis showed the p.W215X mutation to be inherited from the mother and the p.R677X mutation from the father. The clinical information is essential not only to arrive at a correct diagnosis in fetuses with pathologic ultrasound findings, but also to offer a proper genetic counseling to the parents and their relatives.This work has been sponsored by Fundacion Ramón Areces (4715/001) and CIBERER from the Instituto de Salud Carlos III (06/07/0036).Peer Reviewe