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Arnold Munnich - One of the best experts on this subject based on the ideXlab platform.
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ADAMTS10 mutations in autosomal recessive Weill-Marchesani Syndrome.
American journal of human genetics, 2004Co-Authors: Nathalie Dagoneau, Laurence Faivre, Arnold Munnich, Hélène Dollfus, Yves Alembik, André Mégarbané, Abdulrahman Alswaid, Catherine Benoist-lasselin, Céline Huber, Laurence Legeai-malletAbstract:Weill-Marchesani Syndrome (WMS) is characterized by the association of short stature; brachydactyly; joint stiffness; eye anomalies, including microspherophakia and ectopia of the lenses; and, occasionally, heart defects. We have recently mapped a gene for the autosomal recessive form of WMS to chromosome 19p13.3-p13.2, in a 12.4-cM interval. Here, we report null mutations in a member of the extracellular matrix protease family, the gene encoding ADAMTS10, a disintegrin and metalloprotease with thrombospondin motifs. A total of three distinct mutations were identified in two consanguineous families and in one sporadic WMS case, including one nonsense mutation (R237X) and two splice mutations (1190+1G→A and 810+1G→A). ADAMTS10 expression studies using reverse-transcriptase polymerase chain reaction, northern blot, and dot-blot analyses showed that ADAMTS10 is expressed in skin, fetal chondrocytes, and fetal and adult heart. Moreover, electron microscopy and immunological studies of the skin fibroblasts from the patients confirmed impairment of the extracellular matrix. We conclude, therefore, that ADAMTS10 plays a major role in growth and in skin, lens, and heart development in humans.
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in frame fibrillin 1 gene deletion in autosomal dominant Weill Marchesani Syndrome
Journal of Medical Genetics, 2003Co-Authors: Laurence Faivre, Maurice Godfrey, Mary K Wirtz, Nathalie Dagoneau, Le M Merrer, Gwenaelle Collodberoud, Catherine Boileau, John R. Samples, Robert J. Gorlin, Arnold MunnichAbstract:Weill-Marchesani Syndrome (WMS) is a connective tissue disorder characterised by short stature, brachydactyly, joint stiffness, and characteristic eye anomalies including microspherophakia, ectopia of the lenses, severe myopia, and glaucoma. Both autosomal recessive (AR) and autosomal dominant (AD) modes of inheritance have been described and a gene for AR WMS has recently been mapped to chromosome 19p13.3-p13.2. Here, we report on the exclusion of chromosome 19p13.3-p13.2 in a large AD WMS family and show that, despite clinical homogeneity, AD and AR WMS are genetically heterogeneous entities. Because two AD WMS families were consistent with linkage to chromosome 15q21.1, the fibrillin-1 gene was sequenced and a 24 nt in frame deletion within a latent transforming growth factor-β1 binding protein (LTBP) motif of the fibrillin-1 gene was found in a AD WMS family (exon 41, 5074_5097del). This in frame deletion cosegregated with the disease and was not found in 186 controls. This study strongly suggests that AD WMS and Marfan Syndrome are allelic conditions at the fibrillin-1 locus and adds to the remarkable clinical heterogeneity of type I fibrillinopathies.
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In frame fibrillin-1 gene deletion in autosomal dominant Weill-Marchesani Syndrome
Journal of Medical Genetics, 2003Co-Authors: Laurence Faivre, Maurice Godfrey, Nathalie Dagoneau, Catherine Boileau, John Samples, Martine Le Merrer, J. Gorlin, M. Wirtz, Gwenaelle Collod-beroud, Arnold MunnichAbstract:Weill-Marchesani Syndrome (WMS) is a connective tissue disorder characterised by short stature, brachydactyly, joint stiffness, and characteristic eye anomalies including microspherophakia, ectopia of the lenses, severe myopia, and glaucoma. Both autosomal recessive (AR) and autosomal dominant (AD) modes of inheritance have been described and a gene for AR WMS has recently been mapped to chromosome 19p13.3-p13.2. Here, we report on the exclusion of chromosome 19p13.3-p13.2 in a large AD WMS family and show that, despite clinical homogeneity, AD and AR WMS are genetically heterogeneous entities. Because two AD WMS families were consistent with linkage to chromosome 15q21.1, the fibrillin-1 gene was sequenced and a 24 nt in frame deletion within a latent transforming growth factor-beta1 binding protein (LTBP) motif of the fibrillin-1 gene was found in a AD WMS family (exon 41, 5074_5097del). This in frame deletion cosegregated with the disease and was not found in 186 controls. This study strongly suggests that AD WMS and Marfan Syndrome are allelic conditions at the fibrillin-1 locus and adds to the remarkable clinical heterogeneity of type I fibrillinopathies.
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Homozygosity mapping of a Weill-Marchesani Syndrome locus to chromosome 19p13.3-p13.2
Human Genetics, 2002Co-Authors: Laurence Faivre, André Mégarbané, Abdulrahman Alswaid, Louise Zylberberg, Noura Aldohayan, Ana Campos-xavier, Delphine Bacq, Laurence Legeai-mallet, Jacky Bonaventure, Arnold MunnichAbstract:Weill-Marchesani Syndrome (WMS) is a rare disease characterized by short stature, brachydactyly, joint stiffness, and characteristic eye abnormalities, including microspherophakia, ectopia lentis, and glaucoma. Both autosomal recessive and autosomal dominant modes of inheritance have been described in association with WMS. We have performed a genome-wide search in two large consanguineous families of Lebanese and Saudian origin consistent with an autosomal recessive mode of inheritance. Here, we report the linkage of the disease gene to chromosome 19p13.3-p13.2 (Zmax=5.99 at θ=0 at locus D19S906). A recombination event between loci D19S905 and D19S901 defines the distal boundary, and a second recombination event between loci D19S221 and D19S840 defines the proximal boundary of the genetic interval encompassing the WMS gene (12.4 cM). We hope that our ongoing studies will lead to the identification of the disease-causing gene.
Laurence Faivre - One of the best experts on this subject based on the ideXlab platform.
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ADAMTS10 mutations in autosomal recessive Weill-Marchesani Syndrome.
American journal of human genetics, 2004Co-Authors: Nathalie Dagoneau, Laurence Faivre, Arnold Munnich, Hélène Dollfus, Yves Alembik, André Mégarbané, Abdulrahman Alswaid, Catherine Benoist-lasselin, Céline Huber, Laurence Legeai-malletAbstract:Weill-Marchesani Syndrome (WMS) is characterized by the association of short stature; brachydactyly; joint stiffness; eye anomalies, including microspherophakia and ectopia of the lenses; and, occasionally, heart defects. We have recently mapped a gene for the autosomal recessive form of WMS to chromosome 19p13.3-p13.2, in a 12.4-cM interval. Here, we report null mutations in a member of the extracellular matrix protease family, the gene encoding ADAMTS10, a disintegrin and metalloprotease with thrombospondin motifs. A total of three distinct mutations were identified in two consanguineous families and in one sporadic WMS case, including one nonsense mutation (R237X) and two splice mutations (1190+1G→A and 810+1G→A). ADAMTS10 expression studies using reverse-transcriptase polymerase chain reaction, northern blot, and dot-blot analyses showed that ADAMTS10 is expressed in skin, fetal chondrocytes, and fetal and adult heart. Moreover, electron microscopy and immunological studies of the skin fibroblasts from the patients confirmed impairment of the extracellular matrix. We conclude, therefore, that ADAMTS10 plays a major role in growth and in skin, lens, and heart development in humans.
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in frame fibrillin 1 gene deletion in autosomal dominant Weill Marchesani Syndrome
Journal of Medical Genetics, 2003Co-Authors: Laurence Faivre, Maurice Godfrey, Mary K Wirtz, Nathalie Dagoneau, Le M Merrer, Gwenaelle Collodberoud, Catherine Boileau, John R. Samples, Robert J. Gorlin, Arnold MunnichAbstract:Weill-Marchesani Syndrome (WMS) is a connective tissue disorder characterised by short stature, brachydactyly, joint stiffness, and characteristic eye anomalies including microspherophakia, ectopia of the lenses, severe myopia, and glaucoma. Both autosomal recessive (AR) and autosomal dominant (AD) modes of inheritance have been described and a gene for AR WMS has recently been mapped to chromosome 19p13.3-p13.2. Here, we report on the exclusion of chromosome 19p13.3-p13.2 in a large AD WMS family and show that, despite clinical homogeneity, AD and AR WMS are genetically heterogeneous entities. Because two AD WMS families were consistent with linkage to chromosome 15q21.1, the fibrillin-1 gene was sequenced and a 24 nt in frame deletion within a latent transforming growth factor-β1 binding protein (LTBP) motif of the fibrillin-1 gene was found in a AD WMS family (exon 41, 5074_5097del). This in frame deletion cosegregated with the disease and was not found in 186 controls. This study strongly suggests that AD WMS and Marfan Syndrome are allelic conditions at the fibrillin-1 locus and adds to the remarkable clinical heterogeneity of type I fibrillinopathies.
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In frame fibrillin-1 gene deletion in autosomal dominant Weill-Marchesani Syndrome
Journal of Medical Genetics, 2003Co-Authors: Laurence Faivre, Maurice Godfrey, Nathalie Dagoneau, Catherine Boileau, John Samples, Martine Le Merrer, J. Gorlin, M. Wirtz, Gwenaelle Collod-beroud, Arnold MunnichAbstract:Weill-Marchesani Syndrome (WMS) is a connective tissue disorder characterised by short stature, brachydactyly, joint stiffness, and characteristic eye anomalies including microspherophakia, ectopia of the lenses, severe myopia, and glaucoma. Both autosomal recessive (AR) and autosomal dominant (AD) modes of inheritance have been described and a gene for AR WMS has recently been mapped to chromosome 19p13.3-p13.2. Here, we report on the exclusion of chromosome 19p13.3-p13.2 in a large AD WMS family and show that, despite clinical homogeneity, AD and AR WMS are genetically heterogeneous entities. Because two AD WMS families were consistent with linkage to chromosome 15q21.1, the fibrillin-1 gene was sequenced and a 24 nt in frame deletion within a latent transforming growth factor-beta1 binding protein (LTBP) motif of the fibrillin-1 gene was found in a AD WMS family (exon 41, 5074_5097del). This in frame deletion cosegregated with the disease and was not found in 186 controls. This study strongly suggests that AD WMS and Marfan Syndrome are allelic conditions at the fibrillin-1 locus and adds to the remarkable clinical heterogeneity of type I fibrillinopathies.
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Homozygosity mapping of a Weill-Marchesani Syndrome locus to chromosome 19p13.3-p13.2
Human Genetics, 2002Co-Authors: Laurence Faivre, André Mégarbané, Abdulrahman Alswaid, Louise Zylberberg, Noura Aldohayan, Ana Campos-xavier, Delphine Bacq, Laurence Legeai-mallet, Jacky Bonaventure, Arnold MunnichAbstract:Weill-Marchesani Syndrome (WMS) is a rare disease characterized by short stature, brachydactyly, joint stiffness, and characteristic eye abnormalities, including microspherophakia, ectopia lentis, and glaucoma. Both autosomal recessive and autosomal dominant modes of inheritance have been described in association with WMS. We have performed a genome-wide search in two large consanguineous families of Lebanese and Saudian origin consistent with an autosomal recessive mode of inheritance. Here, we report the linkage of the disease gene to chromosome 19p13.3-p13.2 (Zmax=5.99 at θ=0 at locus D19S906). A recombination event between loci D19S905 and D19S901 defines the distal boundary, and a second recombination event between loci D19S221 and D19S840 defines the proximal boundary of the genetic interval encompassing the WMS gene (12.4 cM). We hope that our ongoing studies will lead to the identification of the disease-causing gene.
Dirk Hubmacher - One of the best experts on this subject based on the ideXlab platform.
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A Novel ADAMTS17 Variant That Causes Weill-Marchesani Syndrome 4 Alters fibrillin-1 and Collagen Type I Deposition in the Extracellular Matrix
Matrix biology : journal of the International Society for Matrix Biology, 2019Co-Authors: Stylianos Z. Karoulias, Aude Beyens, Zerina Balic, Sofie Symoens, Anthony Vandersteen, Andrea L. Rideout, John Dickinson, Bert Callewaert, Dirk HubmacherAbstract:Weill-Marchesani Syndrome (WMS) is a rare genetic disorder that affects the musculoskeletal system, the eye, and the cardiovascular system. Individuals with WMS present with short stature, joint contractures, thick skin, microspherophakia, small and dislocated lenses, and cardiac valve anomalies. WMS can be caused by recessive mutations in ADAMTS10 (WMS 1), ADAMTS17 (WMS 4), or LTBP2 (WMS 3), or by dominant mutations in fibrillin-1 (FBN1) (WMS 2); all genes encode secreted extracellular matrix (ECM) proteins. Individuals with WMS 4 due to ADAMTS17 mutations appear to have less severe cardiac involvement and present predominantly with the musculoskeletal and ocular features of WMS. ADAMTS17 is a member of the ADAMTS family of secreted proteases and directly binds to fibrillins. Here we report a novel pathogenic variant in ADAMTS17 that causes WMS 4 in an individual with short stature, brachydactyly, and small, spherical, and dislocated lenses. We provide biochemical and cell biological insights in the pathomechanisms of WMS 4, which also suggest potential biological functions for ADAMTS17. We show that the variant in ADAMTS17 prevents its secretion and we found intracellular accumulation of fibrillin-1 and collagen type I in patient-derived skin fibroblasts. In accordance, transmission electron microscopy revealed elastic fiber abnormalities, decreased collagen fibril diameters, and intracellular collagen accumulation in the dermis of the proband. Together, the data indicate a possible role for ADAMTS17 in the secretion of fibrillin-1 and collagen type I or in their early assembly in the pericellular matrix or the ECM.
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ADAMTS proteins as modulators of microfibril formation and function
Matrix Biology, 2015Co-Authors: Dirk Hubmacher, Sulabha S. ApteAbstract:The ADAMTS (a disintegrin-like and metalloproteinase domain with thrombospondin-type 1 motifs) protein superfamily includes 19 secreted metalloproteases and 7 secreted ADAMTS-like (ADAMTSL) glycoproteins. The possibility of functional linkage between ADAMTS proteins and fibrillin microfibrils was first revealed by a human genetic consilience, in which mutations in ADAMTS10, ADAMTS17, ADAMTSL2 and ADAMTSL4 were found to phenocopy rare genetic disorders caused by mutations affecting fibrillin-1 (FBN1), the major microfibril component in adults. The manifestations of these ADAMTS gene disorders in humans and animals suggested that they participated in the structural and regulatory roles of microfibrils. Whereas two such disorders, Weill–Marchesani Syndrome 1 and Weill–Marchesani-like Syndrome involve proteases (ADAMTS10 and ADAMTS17, respectively), geleophysic dysplasia and isolated ectopia lentis in humans involve ADAMTSL2 and ADAMTSL4, respectively, which are not proteases. In addition to broadly similar dysmorphology, individuals affected by Weill–Marchesani Syndrome 1, Weill–Marchesani-like Syndrome or geleophysic dysplasia each show characteristic anomalies suggesting molecule-, tissue-, or context-specific functions for the respective ADAMTS proteins. Ectopia lentis occurs in each of these conditions except geleophysic dysplasia, and is due to a defect in the ciliary zonule, which is predominantly composed of FBN1 microfibrils. Together, this strongly suggests that ADAMTS proteins are involved either in microfibril assembly, stability, and anchorage, or the formation of function-specific supramolecular networks having microfibrils as their foundation. Here, the genetics and molecular biology of this subset of ADAMTS proteins is discussed from the perspective of how they might contribute to fully functional or function-specific microfibrils.
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Genetic and functional linkage between ADAMTS superfamily proteins and fibrillin-1: a novel mechanism influencing microfibril assembly and function
Cellular and Molecular Life Sciences, 2011Co-Authors: Dirk Hubmacher, Suneel S. ApteAbstract:Tissue microfibrils contain fibrillin-1 as a major constituent. Microfibrils regulate bioavailability of TGFβ superfamily growth factors and are structurally crucial in the ocular zonule. FBN1 mutations typically cause the Marfan Syndrome, an autosomal dominant disorder manifesting with skeletal overgrowth, aortic aneurysm, and lens dislocation ( ectopia lentis ). Infrequently, FBN1 mutations cause dominantly inherited Weill–Marchesani Syndrome (WMS), isolated ectopia lentis (IEL), or the fibrotic condition, geleophysic dysplasia (GD). Intriguingly, mutations in ADAMTS [a disintegrin-like and metalloprotease (reprolysin-type) with thrombospondin type 1 motif] family members phenocopy these disorders, leading to recessive WMS ( ADAMTS10 ), WMS-like Syndrome ( ADAMTS17 ), IEL ( ADAMTSL4 and ADAMTS17 ) and GD ( ADAMTSL2 ). An ADAMTSL2 founder mutation causes Musladin–Lueke Syndrome, a fibrotic disorder in beagle dogs. The overlapping disease spectra resulting from fibrillin-1 and ADAMTS mutations, interaction of ADAMTS10 and ADAMTSL2 with fibrillin-1, and evidence that these ADAMTS proteins accelerate microfibril biogenesis, constitutes a consilience suggesting that some ADAMTS proteins evolved to provide a novel mechanism regulating microfibril formation and consequently cell behavior.
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biogenesis of extracellular microfibrils multimerization of the fibrillin 1 c terminus into bead like structures enables self assembly
Proceedings of the National Academy of Sciences of the United States of America, 2008Co-Authors: Dirk Hubmacher, Ehab I Elhallous, Mari T Kaartinen, Valentin Nelea, Dieter P ReinhardtAbstract:Microfibrils are essential elements in elastic and nonelastic tissues contributing to homeostasis and growth factor regulation. Fibrillins form the core of these multicomponent assemblies. Various human genetic disorders, the fibrillinopathies, arise from mutations in fibrillins and are frequently associated with aberrant microfibril assembly. These disorders include Marfan Syndrome, Weill–Marchesani Syndrome, Beals Syndrome, and others. Although homotypic and heterotypic fibrillin self-interactions are considered to provide critical initial steps, the detailed mechanisms for microfibril assembly are unknown. We show here that the C-terminal recombinant half of fibrillin-1 assembles into disulfide-bonded multimeric globular structures with peripheral arms and a dense core. These globules are similar to the beaded structures observed in microfibrils isolated from tissues. Only these C-terminal fibrillin-1 multimers interacted strongly with the fibrillin-1 N terminus, whereas the monomers showed very little self-interaction activity. The multimers strongly inhibited microfibril formation in cell culture, providing evidence that these recombinant assemblies can also interact with endogenous fibrillin-1. The C-terminal self-interaction site was fine-mapped to the last three calcium-binding EGF domains in fibrillin-1. These results suggest a new mechanism for microfibril formation where fibrillin-1 first oligomerizes via its C terminus before the partially or fully assembled bead-like structures can further interact with other beads via the fibrillin-1 N termini.
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biogenesis of extracellular microfibrils multimerization of the fibrillin 1 c terminus into bead like structures enables self assembly
Proceedings of the National Academy of Sciences of the United States of America, 2008Co-Authors: Dirk Hubmacher, Ehab I Elhallous, Mari T Kaartinen, Valentin Nelea, Dieter P ReinhardtAbstract:Microfibrils are essential elements in elastic and nonelastic tissues contributing to homeostasis and growth factor regulation. Fibrillins form the core of these multicomponent assemblies. Various human genetic disorders, the fibrillinopathies, arise from mutations in fibrillins and are frequently associated with aberrant microfibril assembly. These disorders include Marfan Syndrome, Weill–Marchesani Syndrome, Beals Syndrome, and others. Although homotypic and heterotypic fibrillin self-interactions are considered to provide critical initial steps, the detailed mechanisms for microfibril assembly are unknown. We show here that the C-terminal recombinant half of fibrillin-1 assembles into disulfide-bonded multimeric globular structures with peripheral arms and a dense core. These globules are similar to the beaded structures observed in microfibrils isolated from tissues. Only these C-terminal fibrillin-1 multimers interacted strongly with the fibrillin-1 N terminus, whereas the monomers showed very little self-interaction activity. The multimers strongly inhibited microfibril formation in cell culture, providing evidence that these recombinant assemblies can also interact with endogenous fibrillin-1. The C-terminal self-interaction site was fine-mapped to the last three calcium-binding EGF domains in fibrillin-1. These results suggest a new mechanism for microfibril formation where fibrillin-1 first oligomerizes via its C terminus before the partially or fully assembled bead-like structures can further interact with other beads via the fibrillin-1 N termini.
Puya Gharahkhani - One of the best experts on this subject based on the ideXlab platform.
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potential modifying loci associated with primary lens luxation pedal hyperkeratosis and ocular phenotypes in miniature bull terriers
Investigative Ophthalmology & Visual Science, 2015Co-Authors: Puya Gharahkhani, C A Oleary, David L Duffy, M T KyawtannerAbstract:PURPOSE. Primary lens luxation (PLL) in dogs is an inherited disease in which the lens is displaced from its normal position. A truncating mutation in the ADAMTS17 orthologue on CFA03 is reported to cause PLL in several breeds, mostly terriers. However, the complex inheritance pattern of PLL in miniature bull terriers (MBTs) suggests that other loci may have a modifying effect on the ADAMTS17 mutation. This study aimed to detect such loci increasing risk of PLL in Australian MBTs. METHODS. More than 170,000 single-nucleotide polymorphisms (SNP) across the canine genome were genotyped in 23 PLL-affected and 73 normal Australian MBT, and association between the PLL phenotype and the genetic markers was investigated by using general mixed effects Cox model survival analysis. RESULTS. The highest association peaks, other than that associated with the ADAMTS17 mutation (P = 2.2e-05), were SNP BICF2G630420272 located at 62.2 Mb on chromosome 15 (P = 7.8e-05) and the region between 30 Mb and 32.5 Mb on chromosome 1 (P = 9.3e-05). Joint analysis showed that the PLL-associated allele of the BICF2G630420272 SNP increased risk of PLL in the presence of the ADAMTS17 mutation (P = 8.117e-04). Candidate genes in the two regions of interest included CPE on chromosome 15 and CTGF on chromosome 1. The ADAMTS17 mutation was also associated with abnormal foot and nail shapes, pedal hyperkeratosis, and persistent pupillary membranes. CONCLUSIONS. Two loci with potentially enhancing effects on the ADAMTS17 mutation were associated with PLL in Australian MBTs. Association of the ADAMTS17 mutation with possible pedal skeletal abnormalities in MBTs supports PLL in this breed and Weill-Marchesani Syndrome-like disease in humans as being homologous diseases.
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an adamts17 splice donor site mutation in dogs with primary lens luxation
Investigative Ophthalmology & Visual Science, 2010Co-Authors: Fabiana H G Farias, Gary S Johnson, J F Taylor, Elizabeth A Giuliano, Martin L Katz, Douglas N Sanders, Robert D Schnabel, Stephanie D Mckay, Shahnawaz Khan, Puya GharahkhaniAbstract:PURPOSE. To identify the genetic cause of isolated canine ectopia lentis, a well-characterized veterinary disease commonly referred to as primary lens luxation (PLL) and to compare the canine disease with a newly described human Weill-Marchesani Syndrome (WMS)-like disease of similar genetic etiology. METHODS. Genomewide association analysis and fine mapping by homozygosity were used to identify the chromosomal segment harboring the PLL locus. The resequencing of a regional candidate gene was used to discover a mutation in a splice donor site predicted to cause exon skipping. Exon skipping was confirmed by reverse transcription-polymerase chain reaction amplification of RNA isolated from PLL-affected eyes and from skin fibroblast cultures from PLL-affected dogs. An allelic discrimination assay was used to genotype individual dogs at the splice donor site mutation. RESULTS. The PLL locus was mapped to a 664-kb region of canine chromosome 3 containing regional candidate gene ADAMTS17. Resequencing ADAMTS17 revealed a GT→AT splice-donor-site mutation at the 5' end of intron 10. The predicted exon 10 skipping and resultant frame shift were confirmed with RNA derived from PLL-affected dogs. The ADAMTS17 mutation was significantly associated with clinical PLL in three different dog breeds. CONCLUSIONS. A truncating mutation in canine ADAMTS17 causes PLL, a well-characterized veterinary disease, which can now be compared to a recently described rare WMS-like disease caused by truncating mutations of the human ADAMTS17 ortholog.
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An ADAMTS17 Splice Donor Site Mutation in Dogs with Primary Lens Luxation
2010Co-Authors: Fabiana H G Farias, Gary S Johnson, J F Taylor, Martin L Katz, Douglas N Sanders, Robert D Schnabel, Stephanie D Mckay, Shahnawaz Khan, Elizabeth Giuliano, Puya GharahkhaniAbstract:PURPOSE. To identify the genetic cause of isolated canine ectopia lentis, a well-characterized veterinary disease commonly referred to as primary lens luxation (PLL) and to compare the canine disease with a newly described human Weill-Marchesani Syndrome (WMS)-like disease of similar genetic etiology. METHODS. Genomewide association analysis and fine mapping by homozygosity were used to identify the chromosomal segment harboring the PLL locus. The resequencing of a regional candidate gene was used to discover a mutation in a splice donor site predicted to cause exon skipping. Exon skipping was confirmed by reverse transcription-polymerase chain reaction amplification of RNA isolated from PLL-affected eyes and from skin fibroblast cultures from PLL-affected dogs. An allelic discrimination assay was used to genotype individual dogs at the splice donor site mutation. RESULTS. The PLL locus was mapped to a 664-kb region of canine chromosome 3 containing regional candidate gene ADAMTS17. Resequencing ADAMTS17 revealed a GT3 AT splice-donor-site mutation at the 5Ј end of intron 10. The predicted exon 10 skipping and resultant frame shift were confirmed with RNA derived from PLL-affected dogs. The ADAMTS17 mutation was significantly associated with clinical PLL in three different dog breeds. CONCLUSIONS. A truncating mutation in canine ADAMTS17 causes PLL, a well-characterized veterinary disease, which can now be compared to a recently described rare WMS-like disease caused by truncating mutations of the human ADAMTS17 ortholog. (Invest Ophthalmol Vis Sci
Nathalie Dagoneau - One of the best experts on this subject based on the ideXlab platform.
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ADAMTS10 mutations in autosomal recessive Weill-Marchesani Syndrome.
American journal of human genetics, 2004Co-Authors: Nathalie Dagoneau, Laurence Faivre, Arnold Munnich, Hélène Dollfus, Yves Alembik, André Mégarbané, Abdulrahman Alswaid, Catherine Benoist-lasselin, Céline Huber, Laurence Legeai-malletAbstract:Weill-Marchesani Syndrome (WMS) is characterized by the association of short stature; brachydactyly; joint stiffness; eye anomalies, including microspherophakia and ectopia of the lenses; and, occasionally, heart defects. We have recently mapped a gene for the autosomal recessive form of WMS to chromosome 19p13.3-p13.2, in a 12.4-cM interval. Here, we report null mutations in a member of the extracellular matrix protease family, the gene encoding ADAMTS10, a disintegrin and metalloprotease with thrombospondin motifs. A total of three distinct mutations were identified in two consanguineous families and in one sporadic WMS case, including one nonsense mutation (R237X) and two splice mutations (1190+1G→A and 810+1G→A). ADAMTS10 expression studies using reverse-transcriptase polymerase chain reaction, northern blot, and dot-blot analyses showed that ADAMTS10 is expressed in skin, fetal chondrocytes, and fetal and adult heart. Moreover, electron microscopy and immunological studies of the skin fibroblasts from the patients confirmed impairment of the extracellular matrix. We conclude, therefore, that ADAMTS10 plays a major role in growth and in skin, lens, and heart development in humans.
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in frame fibrillin 1 gene deletion in autosomal dominant Weill Marchesani Syndrome
Journal of Medical Genetics, 2003Co-Authors: Laurence Faivre, Maurice Godfrey, Mary K Wirtz, Nathalie Dagoneau, Le M Merrer, Gwenaelle Collodberoud, Catherine Boileau, John R. Samples, Robert J. Gorlin, Arnold MunnichAbstract:Weill-Marchesani Syndrome (WMS) is a connective tissue disorder characterised by short stature, brachydactyly, joint stiffness, and characteristic eye anomalies including microspherophakia, ectopia of the lenses, severe myopia, and glaucoma. Both autosomal recessive (AR) and autosomal dominant (AD) modes of inheritance have been described and a gene for AR WMS has recently been mapped to chromosome 19p13.3-p13.2. Here, we report on the exclusion of chromosome 19p13.3-p13.2 in a large AD WMS family and show that, despite clinical homogeneity, AD and AR WMS are genetically heterogeneous entities. Because two AD WMS families were consistent with linkage to chromosome 15q21.1, the fibrillin-1 gene was sequenced and a 24 nt in frame deletion within a latent transforming growth factor-β1 binding protein (LTBP) motif of the fibrillin-1 gene was found in a AD WMS family (exon 41, 5074_5097del). This in frame deletion cosegregated with the disease and was not found in 186 controls. This study strongly suggests that AD WMS and Marfan Syndrome are allelic conditions at the fibrillin-1 locus and adds to the remarkable clinical heterogeneity of type I fibrillinopathies.
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In frame fibrillin-1 gene deletion in autosomal dominant Weill-Marchesani Syndrome
Journal of Medical Genetics, 2003Co-Authors: Laurence Faivre, Maurice Godfrey, Nathalie Dagoneau, Catherine Boileau, John Samples, Martine Le Merrer, J. Gorlin, M. Wirtz, Gwenaelle Collod-beroud, Arnold MunnichAbstract:Weill-Marchesani Syndrome (WMS) is a connective tissue disorder characterised by short stature, brachydactyly, joint stiffness, and characteristic eye anomalies including microspherophakia, ectopia of the lenses, severe myopia, and glaucoma. Both autosomal recessive (AR) and autosomal dominant (AD) modes of inheritance have been described and a gene for AR WMS has recently been mapped to chromosome 19p13.3-p13.2. Here, we report on the exclusion of chromosome 19p13.3-p13.2 in a large AD WMS family and show that, despite clinical homogeneity, AD and AR WMS are genetically heterogeneous entities. Because two AD WMS families were consistent with linkage to chromosome 15q21.1, the fibrillin-1 gene was sequenced and a 24 nt in frame deletion within a latent transforming growth factor-beta1 binding protein (LTBP) motif of the fibrillin-1 gene was found in a AD WMS family (exon 41, 5074_5097del). This in frame deletion cosegregated with the disease and was not found in 186 controls. This study strongly suggests that AD WMS and Marfan Syndrome are allelic conditions at the fibrillin-1 locus and adds to the remarkable clinical heterogeneity of type I fibrillinopathies.