The Experts below are selected from a list of 93 Experts worldwide ranked by ideXlab platform
Jan Hellemans - One of the best experts on this subject based on the ideXlab platform.
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the heterozygous lemd3 gt mouse is not a murine model for osteopoikilosis in humans
Calcified Tissue International, 2009Co-Authors: Annelies Dheedene, Steven Deleye, Steven Staelens, Stefaan Vandenberghe, Jan Hellemans, Geert MortierAbstract:Osteopoikilosis and the Buschke-Ollendorff Syndrome are skeletal dysplasias with hyperostotic lesions in the long bones. These disorders are caused by heterozygous loss-of-function mutations in the LEMD3 gene. LEMD3 codes for a protein of the inner nuclear membrane that, through interaction with R-SMADs, antagonizes the BMP and TGFβ1 pathway. It is suggested that the hyperostotic lesions in these disorders are caused by enhanced BMP and TGFβ1 signaling. The exact mechanism by which mutations in the LEMD3 gene lead to these bone lesions has not yet been unraveled precisely. To further assess this, an Lemd3 gene–trapped mouse was created in a gene-trapping program by Baygenomics. To investigate whether the heterozygous gene-trapped mouse is a good model for osteopoikilosis in humans, we studied these mice radiologically with high-resolution micro-computed tomography (microCT) and histologically. X-ray images were evaluated by a trained radiologist, but no typical osteopoikilosis lesions could be recognized. On all microCT reconstructed images a 3D cortical and trabecular quantitative analysis was performed, investigating different histomorphometric parameters ranging from percent bone volume, bone surface/volume ratio over trabecular thickness, separation, number, and pattern factor to structure model index and fractal dimension. No significant differences were found after a t-test statistical analysis. Also, histological analysis did not reveal lesions typical for osteopoikilosis. We conclude that the heterozygous Lemd3 gene–trapped mouse is not a good model to study osteopoikilosis and the Buschke-Ollendorff Syndrome.
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germline lemd3 mutations are rare in sporadic patients with isolated melorheostosis
Human Mutation, 2006Co-Authors: Jan Hellemans, Lina Basel, Michael Wright, Klaus W. Kjaer, Peter Verdonk, Andreas R Janecke, Philippe Debeer, Celia Moss, Ravi Savarirayan, Johannes RothAbstract:To further explore the allelic heterogeneity within the group of LEMD3-related disorders, we have screened a larger series of patients including 5 probands with osteopoikilosis or Buschke-Ollendorff Syndrome (BOS), 2 families with the co-occurrence of melorheostosis and BOS, and 12 unrelated patients with isolated melorheostosis. Seven novel LEMD3 mutations were identified, all predicted to result in loss-of-function of the protein. We confirm that loss-of-function mutations in the LEMD3 gene can result in either osteopoikilosis or BOS. However, LEMD3 germline mutations were only found in two melorheostosis patients belonging to a different BOS family and one sporadic patient with melorheostosis. The additional presence of osteopoikilosis lesions in these patients seemed to distinguish them from the group of sporadic melorheostosis patients where no germline LEMD3 mutation was identified. Somatic mosaicism for a LEMD3 mutation in the latter group was also not observed, and therefore we must conclude that the genetic defect in the majority of sporadic and isolated melorheostosis remains unknown. © 2006 Wiley-Liss, Inc.
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loss of function mutations in lemd3 result in osteopoikilosis buschke ollendorff Syndrome and melorheostosis
Nature Genetics, 2004Co-Authors: Jan Hellemans, Olena Preobrazhenska, Teresa Costa, Katrien Janssens, Bjorn Menten, Andy Willaert, Stefan Vermeulen, Peter Verdonk, Philippe Debeer, Ravi SavarirayanAbstract:Osteopoikilosis, Buschke-Ollendorff Syndrome (BOS) and melorheostosis are disorders characterized by increased bone density1. The occurrence of one or more of these phenotypes in the same individual or family suggests that these entities might be allelic2,3,4. We collected data from three families in which affected individuals had osteopoikilosis with or without manifestations of BOS or melorheostosis. A genome-wide linkage analysis in these families, followed by the identification of a microdeletion in an unrelated individual with these diseases, allowed us to map the gene that is mutated in osteopoikilosis. All the affected individuals that we investigated were heterozygous with respect to a loss-of-function mutation in LEMD3 (also called MAN1), which encodes an inner nuclear membrane protein. A somatic mutation in the second allele of LEMD3 could not be identified in fibroblasts from affected skin of an individual with BOS and an individual with melorheostosis. XMAN1, the Xenopus laevis ortholog, antagonizes BMP signaling during embryogenesis5. In this study, LEMD3 interacted with BMP and activin-TGFβ receptor–activated Smads and antagonized both signaling pathways in human cells.
B. Paul Wordsworth - One of the best experts on this subject based on the ideXlab platform.
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novel and recurrent germline lemd3 mutations causing buschke ollendorff Syndrome and osteopoikilosis but not isolated melorheostosis
Clinical Genetics, 2009Co-Authors: Y Zhang, Giulio Ferranti, Marco Castori, Mauro Paradisi, B. Paul WordsworthAbstract:Mutations in the LEMD3 gene were recently incriminated in Buschke― Ollendorff Syndrome (BOS) and osteopoikilosis, with or without melorheostosis. The relationship of this gene with isolated sporadic melorheostosis is less clear. We investigated LEMD3 in a two-generation BOS family showing an extremely variable expression of the disease, in a sporadic patient with skin features of BOS, and in an additional subject with isolated melorheostosis. We identified two different mutations, both resulting in a premature stop codon, in the two cases of BOS. The mutation (c.2564G>A) reported in the familial case is novel, while that observed in the sporadic case (c.1963C>T) has been previously reported in an American woman with osteopoikilosis and melorheostosis who had a family history of isolated osteopoikilosis. The search for mutations in DNA extracted from the peripheral blood, as well as skin and bone biopsies of the patient with melorheostosis failed to identify any pathogenic change. Our results further expand the LEMD3 mutation repertoire, corroborate the extreme interfamilial and intrafamilial clinical variability of LEMD3 mutations, and underline the lack of a clear phenotype-genotype correlation in BOS. The present study supports the general conclusion that LEMD3 mutations do not contribute to isolated sporadic melorheostosis. The genetic or epigenetic influences that are responsible for the development of melorheostosis require further investigation.
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A Novel LEMD3 Mutation Common to Patients with Osteopoikilosis With and Without Melorheostosis
Calcified Tissue International, 2007Co-Authors: Ana R. Couto, Matthew A Brown, Jacome Bruges-armas, Kay Chapman, C A Peach, B. Paul Wordsworth, Yun ZhangAbstract:Recent studies have reported loss of function mutations in the LEMD3 gene, encoding an inner nuclear membrane protein that influences Smad signaling, as a cause of osteopoikilosis, Buschke-Ollendorff Syndrome, and melorheostosis. We investigated LEMD3 in a three-generation family with osteopoikilosis from the Azores, an affected father and daughter from Ireland with osteopoikilosis (the daughter also had melorheostosis), and two other individuals from the UK with isolated melorheostosis. We found a novel C to T substitution at position 2032 bp (cDNA) in exon 8 of LEMD3 , resulting in a premature stop codon at amino acid position 678. This mutation co-segregates with the osteopoikilosis phenotype in both the Azorean family and the Irish family. It was not detected in any of the six unaffected family members or in 342 healthy Caucasian individuals. No LEMD3 mutations were detected in the two patients with sporadic melorheostosis. The LEMD3 mutation reported was clearly the cause of osteopoikilosis in the two families but its relationship to melorheostosis in one of the family members is still unclear. Perhaps unsurprisingly in what is a segmental disease, we did not find LEMD3 mutations in peripheral-blood-derived DNA from the two other individuals with sporadic melorheostosis. The nature of the additional genetic and/or environmental influences required for the development of melorheostosis in those with osteopoikilosis requires further investigation.
Michael P Whyte - One of the best experts on this subject based on the ideXlab platform.
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deactivating germline mutations in lemd3 cause osteopoikilosis and buschke ollendorff Syndrome but not sporadic melorheostosis
Journal of Bone and Mineral Research, 2006Co-Authors: Steven Mumm, Deborah Wenkert, Xiafang Zhang, William H Mcalister, Richard J Mier, Michael P WhyteAbstract:Autosomal dominant OPK and BOS feature widespread foci of osteosclerotic trabeculae without or with skin lesions, respectively. Occasionally, a larger area of dense bone in OPK or BOS resembles MEL, a sporadic sclerosing disorder primarily involving cortical bone. Others, finding deactivating germline LEMD3 mutations in OPK or BOS, concluded such defects explain all three conditions. We found germline LEMD3 mutations in OPK and BOS but not in sporadic MEL. Introduction: In 2004, others discovered that heterozygous, loss-of-function, germline mutations in the LEMD3 gene (LEMD3 or MAN1) cause both osteopoikilosis (OPK) and Buschke-Ollendorff Syndrome (BOS). OPK is an autosomal dominant, usually benign, skeletal dysplasia featuring multiple, small, especially metaphyseal, oval or round, dense trabecular foci distributed symmetrically throughout the skeleton. BOS combines OPK with connective tissue nevi comprised of collagen and elastin. In some OPK and BOS families, an individual may have relatively large, asymmetric areas of dense cortical bone interpreted as melorheostosis (MEL). MEL, however, classically refers to a sporadic, troublesome skeletal dysostosis featuring large, asymmetric, “flowing hyperostosis” of long bone cortices often with overlying, constricting soft tissue abnormalities. However, a heterozygous germline mutation in LEMD3 was offered to explain MEL. Materials and Methods: We studied 11 unrelated individuals with sclerosing bone disorders where LEMD3 mutation was a potential etiology: familial OPK (1), familial BOS (2), previously reported familial OPK with MEL (1), sporadic MEL (3), sporadic MEL with mixed-sclerosing-bone dystrophy (1), and patients with other unusual sclerosing bone disorders (3). All coding exons and adjacent mRNA splice sites for LEMD3 were amplified by PCR and sequenced using genomic DNA from leukocytes. We did not study lesional tissue from bone or skin. Results: In the OPK family, a heterozygous nonsense mutation (c.1433T>A, p.L478X) was discovered in exon 1. In the two BOS families, a heterozygous nonsense mutation (exon 1, c.1323C>A, p.Y441X) and a heterozygous frame-shift mutation (exon 1, c.332_333insTC) were identified. In the individual with MEL and familial OPK, a heterozygous nonsense mutation (c.1963C>T, p.R655X) was detected in exon 7. However, no LEMD3 mutation was found for any other patient, including all four with sporadic MEL. Conclusions: We confirm that OPK and BOS individuals, including those with MEL-like lesions, have heterozygous, deactivating, germline LEMD3 mutations. However, MEL remains of unknown etiology.
Geert Mortier - One of the best experts on this subject based on the ideXlab platform.
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the heterozygous lemd3 gt mouse is not a murine model for osteopoikilosis in humans
Calcified Tissue International, 2009Co-Authors: Annelies Dheedene, Steven Deleye, Steven Staelens, Stefaan Vandenberghe, Jan Hellemans, Geert MortierAbstract:Osteopoikilosis and the Buschke-Ollendorff Syndrome are skeletal dysplasias with hyperostotic lesions in the long bones. These disorders are caused by heterozygous loss-of-function mutations in the LEMD3 gene. LEMD3 codes for a protein of the inner nuclear membrane that, through interaction with R-SMADs, antagonizes the BMP and TGFβ1 pathway. It is suggested that the hyperostotic lesions in these disorders are caused by enhanced BMP and TGFβ1 signaling. The exact mechanism by which mutations in the LEMD3 gene lead to these bone lesions has not yet been unraveled precisely. To further assess this, an Lemd3 gene–trapped mouse was created in a gene-trapping program by Baygenomics. To investigate whether the heterozygous gene-trapped mouse is a good model for osteopoikilosis in humans, we studied these mice radiologically with high-resolution micro-computed tomography (microCT) and histologically. X-ray images were evaluated by a trained radiologist, but no typical osteopoikilosis lesions could be recognized. On all microCT reconstructed images a 3D cortical and trabecular quantitative analysis was performed, investigating different histomorphometric parameters ranging from percent bone volume, bone surface/volume ratio over trabecular thickness, separation, number, and pattern factor to structure model index and fractal dimension. No significant differences were found after a t-test statistical analysis. Also, histological analysis did not reveal lesions typical for osteopoikilosis. We conclude that the heterozygous Lemd3 gene–trapped mouse is not a good model to study osteopoikilosis and the Buschke-Ollendorff Syndrome.
Johannes Roth - One of the best experts on this subject based on the ideXlab platform.
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germline lemd3 mutations are rare in sporadic patients with isolated melorheostosis
Human Mutation, 2006Co-Authors: Jan Hellemans, Lina Basel, Michael Wright, Klaus W. Kjaer, Peter Verdonk, Andreas R Janecke, Philippe Debeer, Celia Moss, Ravi Savarirayan, Johannes RothAbstract:To further explore the allelic heterogeneity within the group of LEMD3-related disorders, we have screened a larger series of patients including 5 probands with osteopoikilosis or Buschke-Ollendorff Syndrome (BOS), 2 families with the co-occurrence of melorheostosis and BOS, and 12 unrelated patients with isolated melorheostosis. Seven novel LEMD3 mutations were identified, all predicted to result in loss-of-function of the protein. We confirm that loss-of-function mutations in the LEMD3 gene can result in either osteopoikilosis or BOS. However, LEMD3 germline mutations were only found in two melorheostosis patients belonging to a different BOS family and one sporadic patient with melorheostosis. The additional presence of osteopoikilosis lesions in these patients seemed to distinguish them from the group of sporadic melorheostosis patients where no germline LEMD3 mutation was identified. Somatic mosaicism for a LEMD3 mutation in the latter group was also not observed, and therefore we must conclude that the genetic defect in the majority of sporadic and isolated melorheostosis remains unknown. © 2006 Wiley-Liss, Inc.
