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Gail C. Jackson - One of the best experts on this subject based on the ideXlab platform.
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Pseudoachondroplasia and multiple epiphyseal dysplasia: a 7-year comprehensive analysis of the known disease genes identify novel and recurrent mutations and provides an accurate assessment of their relative contribution.
Human mutation, 2011Co-Authors: Gail C. Jackson, Jacqueline A. Taylor, Martine Le Merrer, Geert Mortier, Lauréane Mittaz-crettol, Juergen Spranger, Valérie Cormier-daire, Christine Hall, Amaka C. OffiahAbstract:Pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED) are relatively common skeletal dysplasias resulting in short-limbed dwarfism, joint pain, and stiffness. PSACH and the largest proportion of autosomal dominant MED (AD-MED) results from mutations in cartilage oligomeric matrix protein (COMP); however, AD-MED is genetically heterogenous and can also result from mutations in matrilin-3 (MATN3) and type IX collagen (COL9A1, COL9A2, and COL9A3). In contrast, autosomal recessive MED (rMED) appears to result exclusively from mutations in sulphate transporter solute carrier family 26 (SLC26A2). The diagnosis of PSACH and MED can be difficult for the nonexpert due to various complications and similarities with other related diseases and often mutation analysis is requested to either confirm or exclude the diagnosis. Since 2003, the European Skeletal Dysplasia Network (ESDN) has used an on-line review system to efficiently diagnose cases referred to the network prior to mutation analysis. In this study, we present the molecular findings in 130 patients referred to ESDN, which includes the identification of novel and recurrent mutations in over 100 patients. Furthermore, this study provides the first indication of the relative contribution of each gene and confirms that they account for the majority of PSACH and MED. Hum Mutat 33:144–157, 2012. © 2011 Wiley Periodicals, Inc.
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Type IX collagen gene mutations can result in multiple epiphyseal dysplasia that is associated with osteochondritis dissecans and a mild myopathy.
American Journal of Medical Genetics Part A, 2010Co-Authors: Gail C. Jackson, D Marcus-soekarman, Irene Stolte-dijkstra, Aad Verrips, Jacqueline A. TaylorAbstract:Multiple epiphyseal dysplasia (MED) is a clinically variable and genetically heterogeneous disease that is characterized by mild short stature and early onset osteoarthritis. Autosomal dominant forms are caused by mutations in the genes that encode type IX collagen, cartilage oligomeric matrix protein, and matrilin-3: COL9A1, COL9A2, COL9A3, COMP, and MATN3, respectively. Splicing mutations have been identified in all three genes encoding type IX collagen and are restricted to specific exons encoding an equivalent region of the COL3 domain in all three alpha(IX) chains. MED has been associated with mild myopathy in some families, in particular one family with a COL9A3 mutation and two families with C-terminal COMP mutations. In this study we have identified COL9A2 mutations in two families with MED that also have osteochondritis dissecans and mild myopathy. This study therefore extends the range of gene-mutations that can cause MED-related myopathy. (c) 2010 Wiley-Liss, Inc.
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RESEARCH ARTICLE Type IX Collagen Gene Mutations Can Result in Multiple Epiphyseal Dysplasia That Is Associated With
2009Co-Authors: Osteochondritis Dissecans, Gail C. Jackson, D Marcus-soekarman, Irene Stolte-dijkstra, Aad Verrips, Jacqueline A. Taylor, Mild A Myopathy, Michael D. BriggsAbstract:Multiple epiphyseal dysplasia (MED) is a clinically variable and genetically heterogeneous disease that is characterized by mild short stature and early onset osteoarthritis. Autosomal domi-nant forms are caused by mutations in the genes that encode type IX collagen, cartilage oligomeric matrix protein, and matrilin-3: COL9A1, COL9A2, COL9A3, COMP, and MATN3, respectively. Splicing mutations have been identified in all three genes encod-ing type IX collagen and are restricted to specific exons encoding an equivalent region of the COL3 domain in all three a(IX) chains. MED has been associated with mild myopathy in some families, in particular one family with a COL9A3 mutation and two families with C-terminal COMP mutations. In this study we have identified COL9A2 mutations in two families with MED that also have osteochondritis dissecans and mild myopathy. This study therefore extends the range of gene-mutations that can cause MED-related myopathy. 2010 Wiley-Liss, Inc. Key words: multiple epiphyseal dysplasia; myopthathy; type IX collagen; cartilage; osteochondritis dissecan
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Missense mutations in the beta strands of the single A-domain of matrilin-3 result in multiple epiphyseal dysplasia.
Journal of medical genetics, 2004Co-Authors: Gail C. Jackson, Eveliina Jakkula, Outi Mäkitie, William G. Cole, Malwina Czarny-ratajczak, Michael Wright, Sarah F. Smithson, Mohnish Suri, Piotr RogalaAbstract:Multiple epiphyseal dysplasia (MED) is a relatively mild and clinically variable osteochondrodysplasia in which the hip and knee joints are most frequently affected. Both autosomal dominant and autosomal recessive forms of MED are recognised. The more severe forms of MED are often described as the “Fairbank type”, whereas the milder cases are known as the “Ribbing type”. However, this classification belies a much greater clinical spectrum in which characteristics such as radiographic features, age of onset, degree of lower limb deformity, stature, and long term morbidity such as osteoarthritis are extremely variable.1–4 It is therefore not surprising that MED is genetically heterogeneous, and to date mutations in six different genes have been shown to cause MED.5,6 Mutations in the genes encoding cartilage oligomeric matrix protein ( COMP ), the α1, α2, and α3 chains of type IX collagen ( COL9A1, COL9A2 , and COL9A3 ) and matrilin-3 ( MATN3 ) all result in autosomal dominant MED,7–11 whereas specific mutations in the sulphate transporter 26A2 ( SLC26A2 /DTDST ) have been shown to result in an autosomal recessive form of MED.12,13 Preliminary genotype–phenotype correlations have suggested that the more severe forms of autosomal dominant MED often result from COMP mutations, while the milder forms are more probably caused by mutations in the genes encoding type IX collagen or matrilin-3.14,15 However, the number of patients available for comparative study, particularly those with type IX collagen and matrilin-3 defects, has remained too limited to date to allow any in depth correlations to be derived. The matrilins are a four member family of extracellular matrix proteins; matrilin-1 and -3 are specifically expressed in cartilaginous tissues, while matrilin-2 and -4 have a wider pattern of expression in a variety of extracellular matrices including non-skeletal tissues.16,17 Each member of the family comprise …
Louis M Kunkel - One of the best experts on this subject based on the ideXlab platform.
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a mutation in the alpha 3 chain of type ix collagen causes autosomal dominant multiple epiphyseal dysplasia with mild myopathy
Proceedings of the National Academy of Sciences of the United States of America, 2000Co-Authors: Carsten G Bonnemann, Frederic Shapiro, Jiann Jiu Wu, Chris A Feener, Teryl G Thompson, Douglas C Anthony, David R Eyre, Basil T Darras, Louis M KunkelAbstract:Multiple epiphyseal dysplasia (MED) is a degenerative cartilage condition shown in some cases to be caused by mutations in genes encoding cartilage oligomeric matrix protein or type IX collagen. We studied a family with autosomal dominant MED affecting predominantly the knee joints and a mild proximal myopathy. Genetic linkage to the COL9A3 locus on chromosome 20q13.3 was established with a peak log10 odds ratio for linkage score of 3.87 for markers D20S93 and D20S164. Reverse transcription–PCR performed on the muscle biopsy revealed aberrant mRNA lacking exon 3, which predicted a protein lacking 12 amino acids from the COL3 domain of α3(IX) collagen. Direct sequencing of genomic DNA confirmed the presence of a splice acceptor mutation in intron 2 of the COL9A3 gene (intervening sequence 2, G-A, -1) only in affected family members. By electron microscopy, chondrocytes from epiphyseal cartilage exhibited dilated rough endoplasmic reticulum containing linear lamellae of alternating electron-dense and electron-lucent material, reflecting abnormal processing of mutant protein. Type IX collagen chains appeared normal in size and quantity but showed defective cross-linking by Western blotting. The novel phenotype of MED and mild myopathy is likely caused by a dominant-negative effect of the exon 3-skipping mutation in the COL9A3 gene. Patients with MED and a waddling gait but minimal radiographic hip involvement should be evaluated for a primary myopathy and a mutation in type IX collagen.
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a mutation in the alpha 3 chain of type ix collagen causes autosomal dominant multiple epiphyseal dysplasia with mild myopathy
Proceedings of the National Academy of Sciences of the United States of America, 2000Co-Authors: Carsten G Bonnemann, Frederic Shapiro, Chris A Feener, Teryl G Thompson, Douglas C Anthony, David R Eyre, Basil T Darras, Gerald F Cox, Louis M KunkelAbstract:Multiple epiphyseal dysplasia (MED) is a degenerative cartilage condition shown in some cases to be caused by mutations in genes encoding cartilage oligomeric matrix protein or type IX collagen. We studied a family with autosomal dominant MED affecting predominantly the knee joints and a mild proximal myopathy. Genetic linkage to the COL9A3 locus on chromosome 20q13.3 was established with a peak log10 odds ratio for linkage score of 3.87 for markers D20S93 and D20S164. Reverse transcription–PCR performed on the muscle biopsy revealed aberrant mRNA lacking exon 3, which predicted a protein lacking 12 amino acids from the COL3 domain of α3(IX) collagen. Direct sequencing of genomic DNA confirmed the presence of a splice acceptor mutation in intron 2 of the COL9A3 gene (intervening sequence 2, G-A, -1) only in affected family members. By electron microscopy, chondrocytes from epiphyseal cartilage exhibited dilated rough endoplasmic reticulum containing linear lamellae of alternating electron-dense and electron-lucent material, reflecting abnormal processing of mutant protein. Type IX collagen chains appeared normal in size and quantity but showed defective cross-linking by Western blotting. The novel phenotype of MED and mild myopathy is likely caused by a dominant-negative effect of the exon 3-skipping mutation in the COL9A3 gene. Patients with MED and a waddling gait but minimal radiographic hip involvement should be evaluated for a primary myopathy and a mutation in type IX collagen.
Richard Wilson - One of the best experts on this subject based on the ideXlab platform.
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comparative proteomic analysis of normal and collagen ix null mouse cartilage reveals altered extracellular matrix composition and novel components of the collagen ix interactome
Journal of Biological Chemistry, 2013Co-Authors: Bent Brachvogel, Frank Zaucke, Manuel Koch, Jeffrey J. Gorman, Münire Dayakli, Emma L. Norris, Keyur A. Dave, Jacek Stermann, John F Bateman, Richard WilsonAbstract:The cartilage extracellular matrix is essential for endochondral bone development and joint function. In addition to the major aggrecan/collagen II framework, the interacting complex of collagen IX, matrilin-3, and cartilage oligomeric matrix protein (COMP) is essential for cartilage matrix stability, as mutations in Col9a1, Col9a2, COL9A3, Comp, and Matn3 genes cause multiple epiphyseal dysplasia, in which patients develop early onset osteoarthritis. In mice, collagen IX ablation results in severely disturbed growth plate organization, hypocellular regions, and abnormal chondrocyte shape. This abnormal differentiation is likely to involve altered cell-matrix interactions but the mechanism is not known. To investigate the molecular basis of the collagen IX null phenotype we analyzed global differences in protein abundance between wild-type and knock-out femoral head cartilage by capillary HPLC tandem mass spectrometry. We identified 297 proteins in 3-day cartilage and 397 proteins in 21-day cartilage. Components that were differentially abundant between wild-type and collagen IX-deficient cartilage included 15 extracellular matrix proteins. Collagen IX ablation was associated with dramatically reduced COMP and matrilin-3, consistent with known interactions. Matrilin-1, matrilin-4, epiphycan, and thrombospondin-4 levels were reduced in collagen IX null cartilage, providing the first in vivo evidence for these proteins belonging to the collagen IX interactome. Thrombospondin-4 expression was reduced at the mRNA level, whereas matrilin-4 was verified as a novel collagen IX-binding protein. Furthermore, changes in TGFβ-induced protein βig-h3 and fibronectin abundance were found in the collagen IX knock-out but not associated with COMP ablation, indicating specific involvement in the abnormal collagen IX null cartilage. In addition, the more widespread expression of collagen XII in the collagen IX-deficient cartilage suggests an attempted compensatory response to the absence of collagen IX. Our differential proteomic analysis of cartilage is a novel approach to identify candidate matrix protein interactions in vivo, underpinning further analysis of mutant cartilage lacking other matrix components or harboring disease-causing mutations.
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Comparative Proteomic Analysis of Normal and Collagen IX Null Mouse Cartilage Reveals Altered Extracellular Matrix Composition and Novel Components of the Collagen IX Interactome
The Journal of biological chemistry, 2013Co-Authors: Bent Brachvogel, Frank Zaucke, Manuel Koch, Jeffrey J. Gorman, Münire Dayakli, Emma L. Norris, Keyur A. Dave, Jacek Stermann, Richard WilsonAbstract:BACKGROUND : Collagen IX is an integral cartilage extracellular matrix component important in skeletal development and joint function. RESULTS : Proteomic analysis and validation studies revealed novel alterations in collagen IX null cartilage. CONCLUSION : Matrilin-4, collagen XII, thrombospondin-4, fibronectin, βig-h3, and epiphycan are components of the in vivo collagen IX interactome. SIGNIFICANCE : We applied a proteomics approach to advance our understanding of collagen IX ablation in cartilage. The cartilage extracellular matrix is essential for endochondral bone development and joint function. In addition to the major aggrecan/collagen II framework, the interacting complex of collagen IX, matrilin-3, and cartilage oligomeric matrix protein (COMP) is essential for cartilage matrix stability, as mutations in Col9a1, Col9a2, COL9A3, Comp, and Matn3 genes cause multiple epiphyseal dysplasia, in which patients develop early onset osteoarthritis. In mice, collagen IX ablation results in severely disturbed growth plate organization, hypocellular regions, and abnormal chondrocyte shape. This abnormal differentiation is likely to involve altered cell-matrix interactions but the mechanism is not known. To investigate the molecular basis of the collagen IX null phenotype we analyzed global differences in protein abundance between wild-type and knock-out femoral head cartilage by capillary HPLC tandem mass spectrometry. We identified 297 proteins in 3-day cartilage and 397 proteins in 21-day cartilage. Components that were differentially abundant between wild-type and collagen IX-deficient cartilage included 15 extracellular matrix proteins. Collagen IX ablation was associated with dramatically reduced COMP and matrilin-3, consistent with known interactions. Matrilin-1, matrilin-4, epiphycan, and thrombospondin-4 levels were reduced in collagen IX null cartilage, providing the first in vivo evidence for these proteins belonging to the collagen IX interactome. Thrombospondin-4 expression was reduced at the mRNA level, whereas matrilin-4 was verified as a novel collagen IX-binding protein. Furthermore, changes in TGFβ-induced protein βig-h3 and fibronectin abundance were found in the collagen IX knock-out but not associated with COMP ablation, indicating specific involvement in the abnormal collagen IX null cartilage. In addition, the more widespread expression of collagen XII in the collagen IX-deficient cartilage suggests an attempted compensatory response to the absence of collagen IX. Our differential proteomic analysis of cartilage is a novel approach to identify candidate matrix protein interactions in vivo, underpinning further analysis of mutant cartilage lacking other matrix components or harboring disease-causing mutations.
Hubert J M Smeets - One of the best experts on this subject based on the ideXlab platform.
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mutations in the type iv collagen α3 col4a3 gene in autosomal recessive alport syndrome
Human Molecular Genetics, 1994Co-Authors: Henny H. Lemmink, Toshlo Mochlzukj, C.h. Schröder, Stephen T. Reeders, Lambertus P Van Den Heuvel, Han G Brunner, Bernard A Van Oost, Alberto Barrientos, Leo A H Monnens, Hubert J M SmeetsAbstract:A group of 22 unrelated patients with sporadic or non-X-linked Alport syndrome were screened for mutations in the non-collagenous domain of the type IV collagen alpha 3 (COL4A3) chain gene. The five 3'-exons of this gene, located on chromosome 2qter, were tested by single strand conformation polymorphism analysis and direct sequencing. One patient was heterozygous and another homozygous (Mochizuki et al., Nature Genetics, in press) for a deletion of five nucleotides. A third patient appeared to be a compound heterozygote for two different nonsense mutations. In two patients and the father of a deceased patient we found a heterozygous substitution of an evolutionary conserved leucine by proline. However, segregation data of the mutation and a COL4A3/COL4A4 CA-repeat marker in their families argued against a causative role of the missense mutation. Even drastic changes of strongly conserved amino acids, as in the Leu36Pro case, may not be significant. Autosomal recessive inheritance due to pathogenic COL4A3 mutations accounts for at least 13% of Alport syndrome cases in this sample. It is concluded that COL4A3 is a major gene in the genetically and clinically heterogeneous Alport syndrome.
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mutations in the type iv collagen α3 col4a3 gene in autosomal recessive alport syndrome
Human Molecular Genetics, 1994Co-Authors: Henny H. Lemmink, Toshlo Mochlzukj, C.h. Schröder, Stephen T. Reeders, Lambertus P Van Den Heuvel, Han G Brunner, Bernard A Van Oost, Alberto Barrientos, Leo A H Monnens, Hubert J M SmeetsAbstract:A group of 22 unrelated patients with sporadic or non-X-linked Alport syndrome were screened for mutations in the non-collagenous domain of the type IV collagen alpha 3 (COL4A3) chain gene. The five 3'-exons of this gene, located on chromosome 2qter, were tested by single strand conformation polymorphism analysis and direct sequencing. One patient was heterozygous and another homozygous (Mochizuki et al., Nature Genetics, in press) for a deletion of five nucleotides. A third patient appeared to be a compound heterozygote for two different nonsense mutations. In two patients and the father of a deceased patient we found a heterozygous substitution of an evolutionary conserved leucine by proline. However, segregation data of the mutation and a COL4A3/COL4A4 CA-repeat marker in their families argued against a causative role of the missense mutation. Even drastic changes of strongly conserved amino acids, as in the Leu36Pro case, may not be significant. Autosomal recessive inheritance due to pathogenic COL4A3 mutations accounts for at least 13% of Alport syndrome cases in this sample. It is concluded that COL4A3 is a major gene in the genetically and clinically heterogeneous Alport syndrome.
Jaana Lohiniva - One of the best experts on this subject based on the ideXlab platform.
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a recurrent r718w mutation in comp results in multiple epiphyseal dysplasia with mild myopathy clinical and pathogenetic overlap with collagen ix mutations
Journal of Medical Genetics, 2003Co-Authors: Eveliina Jakkula, Jaana Lohiniva, Luisa Bonafe, A Capone, M Marti, V Schuster, A Giedion, Georg Eich, Eugen Boltshauser, Leena AlakokkoAbstract:Multiple epiphyseal dysplasia (MED) is clinically and genetically a heterogeneous disorder that affects growth centres and results in delayed and irregular mineralisation of the ossification centres.1,2 Recessively inherited MED (rMED; MIM 226900) accounts for a significant proportion of MED cases and is associated with mutations in the sulphate transporter gene, DTDST/SLC26A2.3,4 More often, MED is inherited as a dominant trait. Thus far, five different genes have been implicated in dominantly inherited MED: the gene for cartilage oligomeric matrix protein, COMP (MIM 600310); the genes for the α1, α2, and α3 chains of collagen IX, COL9A1 (MIM 120165), COL9A2 (MIM 120260), and COL9A3 (MIM 120270); and the gene for matrilin-3, MATN3 (MIM 602109). Patients with the severe forms of MED have short stature and major disability because of joint pain and stiffness. In the milder forms, height can be normal and joint complaints minimal. Mutations in COMP typically lead to the severe forms of dominant MED (MIM 132400) and can also cause a related but more severe disorder—pseudoachondroplasia (PSACH, MIM 177170). COMP is a pentameric extracellular glycoprotein that belongs to the thrombospondin protein family.5–7 It consists of a coiled coil N-terminal domain responsible for pentamerisation, four epidermal growth factor (EGF)-like repeats, eight thrombospondin type 3 (T3) repeats, and a large C-terminal globular domain. Mutations in COMP that cause MED are located in the T3 repeats.1,2 Mutations in these repeats alter the conformation of the protein and affect its ability to bind calcium.8–10 No mutations have been reported in the N-terminal domain or the EGF-like domains in MED. Only four mutations causing MED have been found in the C-terminal domain—two (T585R and T585M) in patients with unclassified MED,1,11 and the other two (R718W and N742fsX743) in patients with “severe MED” …
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radiologic phenotypes in lumbar mr imaging for a gene defect in the COL9A3 gene of type ix collagen
Radiology, 2003Co-Authors: Jaro Karppinen, Petteri Paassilta, Jaana Lohiniva, Harald H H Goring, Eija Paakko, Mauno Kurunlahti, Osmo Tervonen, Pentti Nieminen, Antti Malmivaara, Heikki VanharantaAbstract:PURPOSE: To evaluate whether the COL9A3 tryptophan allele (Trp3 allele) is associated with a specific radiologic phenotype among patients with sciatica. MATERIALS AND METHODS: One hundred fifty-three patients with sciatica were evaluated for the presence of Trp3 allele, Scheuermann disease, intervertebral disk degeneration, Schmorl nodules, dorsal anular tears, hyperintense lesions, and endplate degeneration on sagittal T2-weighted lumbar magnetic resonance images. The Trp3 genotype was determined by means of sequencing the COL9A3 gene. Radiologic phenotypes were evaluated while blinded to the genotype. Scheuermann disease was diagnosed if either endplate irregularities or Schmorl nodules and two of the other three criteria (disk space narrowing, disk dehydration, and wedging of anterior vertebral body margins) were present at three or more adjacent disk levels from T10–11 to L3–4. Disk degeneration was evaluated separately for each disk (T11–12 to L5–S1) and for all disks combined. Frequencies of radiolo...
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A Mutation in COL9A1 Causes Multiple Epiphyseal Dysplasia: Further Evidence for Locus Heterogeneity
American journal of human genetics, 2001Co-Authors: Malwina Czarny-ratajczak, Jaana Lohiniva, Merja Perala, Piotr Rogala, Kazimierz Kozlowski, Liisa Carter, Tim D. Spector, Lukasz Kolodziej, Ulpu Seppänen, Renata GlazarAbstract:Multiple epiphyseal dysplasia (MED) is an autosomal dominantly inherited chondrodysplasia. It is clinically highly heterogeneous, partially because of its complex genetic background. Mutations in four genes, COL9A2, COL9A3, COMP, and MATR3, all coding for cartilage extracellular matrix components (i.e., the alpha2 and alpha 3 chains of collagen IX, cartilage oligomeric matrix protein, and matrilin-3), have been identified in this disease so far, but no mutations have yet been reported in the third collagen IX gene, COL9A1, which codes for the alpha1(IX) chain. MED with apparently recessive inheritance has been reported in some families. A homozygous R279W mutation was recently found in the diastrophic dysplasia sulfate transporter gene, DTDST, in a patient with MED who had a club foot and double-layered patella. The series consisted of 41 probands with MED, 16 of whom were familial and on 4 of whom linkage analyses were performed. Recombination was observed between COL9A1, COL9A2, COL9A3, and COMP and the MED phenotype in two of the families, and between COL9A2, COL9A3, and COMP and the phenotype in the other two families. Screening of COL9A1 for mutations in the two probands from the families in which this gene was not involved in the recombinations failed to identify any disease-causing mutations. The remaining 37 probands were screened for mutations in all three collagen IX genes and in the COMP gene. The probands with talipes deformities or multipartite patella were also screened for the R279W mutation in DTDST. The analysis resulted in identification of three mutations in COMP and one in COL9A1, but none in the other two collagen IX genes. Two of the probands with a multipartite patella had the homozygous DTDST mutation. The results show that mutations in COL9A1 can cause MED, but they also suggest that mutations in COL9A1, COL9A2, COL9A3, COMP, and DTDST are not the major causes of MED and that there exists at least one additional locus.
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identification of a novel common genetic risk factor for lumbar disk disease
JAMA, 2001Co-Authors: Petteri Paassilta, Jaana Lohiniva, Harald H H Goring, Merja Perala, Susanna S Raina, Jaro Karppinen, Markku Hakala, Tiina Palm, Heikki KrogerAbstract:ContextLumbar disk disease (LDD) is one of the most common musculoskeletal diseases, with a prevalence of about 5%. A tryptophan (Trp) allele (Trp2) was recently discovered in the COL9A2 gene that is associated with dominantly inherited LDD but is only present in about 4% of Finnish patients with LDD.ObjectiveTo determine if other collagen IX gene sequence variations play a role in the pathogenesis of LDD.Design and SettingCase-control study conducted from February 1997 to May 1998 at university hospitals in Finland.ParticipantsA total of 171 individuals with LDD (evaluated clinically and by magnetic resonance imaging or computed tomography) and 321 controls without LDD (186 healthy individuals, 83 patients with primary osteoarthritis, 31 with rheumatoid arthritis, and 21 with chondrodysplasias).Main Outcome MeasuresFrequencies of sequence variations covering the entire coding sequences and exon boundaries of the collagen IX genes, COL9A1, COL9A2, and COL9A3, which code for the α1, α2, and α3 chains of the protein, detected by conformation-sensitive gel electrophoresis and confirmed by sequencing, compared between individuals with and without LDD.ResultsMutation analysis of all 3 collagen IX genes resulted in identification of an Arg103→Trp (arginine→tryptophan) substitution in the α3 chain (Trp3 allele). The frequency of the Trp3 allele was 12.2% in LDD cases, excluding 7 individuals who were carriers of the previously identified Gln326→Trp (glutamine→tryptophan) substitution in the α2 chain (Trp2 allele), and was 4.7% among controls. The difference in the frequency was statistically significant (P = .000013). Presence of at least 1 Trp3 allele increases risk of LDD about 3-fold.ConclusionThis study led to the identification of a novel common genetic risk factor for LDD, confirming that genetic risk factors likely play a significant role in LDD.
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Multiple epiphyseal dysplasia: radiographic abnormalities correlated with genotype.
Pediatric radiology, 2001Co-Authors: Sheila Unger, Leena Ala-kokko, Petteri Paassilta, Jaana Lohiniva, Michael D. Briggs, Bernhard Zabel, Ralph S Lachman, David L Rimoin, Paul Holden, Daniel H. CohnAbstract:Multiple epiphyseal dysplasia (MED) is an osteochondrodysplasia characterized clinically by mild short stature and early-onset degenerative joint disease and radiographically by epiphyseal hypoplasia/dysplasia. MED is genetically heterogeneous, with autosomal dominant cases resulting from mutations in at least three genes: the cartilage oligomeric matrix protein (COMP) gene (EDM1) and the COL9A2 (EDM2) and COL9A3 (EDM3) genes of type IX procollagen. We present here a comparison of the radiographic phenotypes of MED patients with type IX collagen gene mutations and those with COMP gene mutations. We reviewed radiographs from two patients with MED produced by COMP mutations, two families with COL9A2 mutations, and one family with a mutation in COL9A3. The data demonstrated that the patients with type IX collagen defects had more severe joint involvement at the knees and relative hip sparing, while the patients with COMP mutations had significant involvement at the capital femoral epiphyses and irregular acetabuli. This pattern of joint involvement was consistent regardless of overall degree of severity of the phenotype.