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Vladimir I. Valtchinov - One of the best experts on this subject based on the ideXlab platform.
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MRI Phenotyping of COL9A2/Trp2 and COL9A3/Trp3 Alleles in Lumbar Disc Disease: A Case-control Study in South-Western Iranian Population Reveals a Significant Trp3-Disease Association in Males.
Spine, 2016Co-Authors: Mohammad H. Bagheri, Amir P. Honarpisheh, Majid Yavarian, Zahra Alavi, Jenifer Siegelman, Vladimir I. ValtchinovAbstract:STUDY DESIGN A case-control study of the Trp2/3 alleles of COL9A2/3 genes and their correlation with occurrence of Lumbar disc disease (DDD) as phenotyped by magnetic resonance imaging. OBJECTIVE To establish a better understanding of relationship between presence of said alleles and occurrence of DDD in South-Western Iranian population. SUMMARY OF BACKGROUND DATA A number of genetic predisposing factors have been identified in elevating the risk of developing DDD. Specifically, the Trp2 and Trp3 alleles of COL9A2 and COL9A3 genes have been suggested as DDD risk variants. METHODS A total of 108 patients (mean age = 41±11.8 yrs, range = 20-66 yrs) with 57 controls (mean age = 35±10.0 yrs, range = 20-58 yrs) participated in the study. The frequency of G/A polymorphism in COL9A2 gene on location 326 on chromosome 1 and G/A/C/ or T polymorphism in 103 location of COL9A3 gene on chromosome 20 was assessed using a PCR short-primer technique. Outcome measure was defined as presence of DDD on MRI. Odds ratios (OR) and 95% confidence intervals (CI) were used to assess the likelihood of DDD given occurrence of Trp2(3). RESULTS Each allele was present in both patients and controls. The Trp2 allele was positive in 28.5% of individuals (31.5% of patients; 22.8% of controls), OR 1.55 (0.71-3.56). The Trp3 allele, the frequency was 23.6% in all patients (26.9% patients; 17.5% controls), OR 1.72 (0.73-4.33). We observed a 5.8-fold increase in the odds of DDD in males when the Trp3 allele was present, OR 5.83 (1.09-9.98), P = 0.0273. CONCLUSION Both Trp2 and Trp3 alleles occurred more frequently compared with other studied ethnicities. The sampled Iranian population exhibited a similar Trp2 frequency to a Southern Chinese population, and Trp3 occurrence to Finnish and Greek population. We found that male patient were much more likely to develop DDD when Trp 3 was present. LEVEL OF EVIDENCE N/A.
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mri phenotyping of COL9A2 trp2 and col9a3 trp3 alleles in lumbar disc disease a case control study in south western iranian population reveals a significant trp3 disease association in males
Spine, 2016Co-Authors: Mohammad H. Bagheri, Amir P. Honarpisheh, Majid Yavarian, Zahra Alavi, Jenifer Siegelman, Vladimir I. ValtchinovAbstract:STUDY DESIGN A case-control study of the Trp2/3 alleles of COL9A2/3 genes and their correlation with occurrence of Lumbar disc disease (DDD) as phenotyped by magnetic resonance imaging. OBJECTIVE To establish a better understanding of relationship between presence of said alleles and occurrence of DDD in South-Western Iranian population. SUMMARY OF BACKGROUND DATA A number of genetic predisposing factors have been identified in elevating the risk of developing DDD. Specifically, the Trp2 and Trp3 alleles of COL9A2 and COL9A3 genes have been suggested as DDD risk variants. METHODS A total of 108 patients (mean age = 41±11.8 yrs, range = 20-66 yrs) with 57 controls (mean age = 35±10.0 yrs, range = 20-58 yrs) participated in the study. The frequency of G/A polymorphism in COL9A2 gene on location 326 on chromosome 1 and G/A/C/ or T polymorphism in 103 location of COL9A3 gene on chromosome 20 was assessed using a PCR short-primer technique. Outcome measure was defined as presence of DDD on MRI. Odds ratios (OR) and 95% confidence intervals (CI) were used to assess the likelihood of DDD given occurrence of Trp2(3). RESULTS Each allele was present in both patients and controls. The Trp2 allele was positive in 28.5% of individuals (31.5% of patients; 22.8% of controls), OR 1.55 (0.71-3.56). The Trp3 allele, the frequency was 23.6% in all patients (26.9% patients; 17.5% controls), OR 1.72 (0.73-4.33). We observed a 5.8-fold increase in the odds of DDD in males when the Trp3 allele was present, OR 5.83 (1.09-9.98), P = 0.0273. CONCLUSION Both Trp2 and Trp3 alleles occurred more frequently compared with other studied ethnicities. The sampled Iranian population exhibited a similar Trp2 frequency to a Southern Chinese population, and Trp3 occurrence to Finnish and Greek population. We found that male patient were much more likely to develop DDD when Trp 3 was present. LEVEL OF EVIDENCE N/A.
Michael D. Briggs - One of the best experts on this subject based on the ideXlab platform.
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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. Taylor, 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 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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Mutations in the known genes are not the major cause of MED; distinctive phenotypic entities among patients with no identified mutations
European Journal of Human Genetics, 2005Co-Authors: Eveliina Jakkula, Michael D. Briggs, Gail C. Jackson, Outi Mäkitie, William G. Cole, Malwina Czarny-ratacjzak, Rita Damignani, Miki Susic, Leena Ala-kokkoAbstract:Multiple epiphyseal dysplasia (MED) is a clinically and genetically heterogeneous chondrodysplasia. Mutations in six genes ( COMP , COL9A1 , COL9A2 , COL9A3 , MATN3 and DTDST ) have been reported, but the genotype–phenotype correlations and the proportions of cases due to mutations in these genes are still not well characterized. We performed a clinical, radiological and molecular analysis of known MED genes on 29 consecutive MED patients. The mutation analysis resulted in identification of the DTDST mutation in four patients (14%), the COMP mutation in three (10%) and the MATN3 mutation in three (10%). Thus, a disease-causing mutation was identified in 10 patients altogether (34%). The phenotypic features observed in the patients with mutations were in accordance with previously described phenotypes, but two new distinct phenotypic entities were identified in patients in whom no mutation was found. One of them was characterized by severe, early-onset dysplasia of the proximal femurs with almost complete absence of the secondary ossification centres and abnormal development of the femoral necks. The other phenotype was characterized by ‘mini-epiphyses’, resulting in severe dysplasia of the proximal femoral heads. The findings suggest that mutations in the known genes are not the major cause of MED and are responsible for less than half of the cases. The existence of additional MED loci is supported by the exclusion of known loci by mutation analysis and finding of specific subgroups among these patients.
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Pseudoachondroplasia and multiple epiphyseal dysplasia: Mutation review, molecular interactions, and genotype to phenotype correlations
Human mutation, 2002Co-Authors: Michael D. Briggs, K ChapmanAbstract:Pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED) constitute a bone dysplasia family, which is both genetically and phenotypically heterogeneous. The disease spectrum ranges from mild MED, which manifests with pain and stiffness in the joints and delayed and irregular ossification of the epiphyses, to the more severe PSACH, which is characterized by marked short stature, deformity of the legs, and ligamentous laxity. PSACH is almost exclusively caused by mutations in cartilage oligomeric matrix protein (COMP) whereas various forms of MED are caused by mutations in the genes encoding COMP, type IX collagen (COL9A1, COL9A2, and COL9A3), matrilin-3 (MATN3), and solute carrier member 26, member 2 gene (SLC26A2). In this review we discuss specific disease-causing mutations and the clustering of these mutations in functionally and structurally important regions of the respective gene products, genotype to phenotype correlations, and the diagnostic relevance of mutation screening in these osteochondrodysplasias.
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Clinical and radiographic features of multiple epiphyseal dysplasia not linked to the COMP or type IX collagen genes
European Journal of Human Genetics, 2001Co-Authors: Geert R Mortier, Kathryn Chapman, Jules L Leroy, Michael D. BriggsAbstract:Multiple epiphyseal dysplasia (MED) is a mild chondrodysplasia affecting the structural integrity of cartilage and causing early-onset osteoarthrosis in adulthood. The condition is genetically heterogeneous. Mutations in the COMP gene and in two genes ( COL9A2; COL9A3 ), coding respectively for the α2(IX) and α3(IX) chains of type IX collagen, can cause the autosomal dominant forms of MED. Mutations in the DTDST gene have recently been identified in a recessive form of MED. However, for the majority of MED cases, the genetic defect still remains undetermined. We report a three-generation family with an autosomal dominant form of MED, characterised by normal stature, joint pain in childhood and early-onset osteoarthrosis, affecting mainly the hips and knees. Based on discordant inheritance among affected individuals linkage of the phenotype to the COMP, COL9A1, COL9A2, COL9A3 genes was excluded. Our study provides evidence that at least another locus, distinct from COL9A1 , is involved in autosomal dominant MED.
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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, Paul Holden, Bernhard Zabel, Ralph S Lachman, David L. Rimoin, 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.
Shiro Ikegawa - One of the best experts on this subject based on the ideXlab platform.
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Novel and recurrent COL11A1 and COL2A1 mutations in the Marshall–Stickler syndrome spectrum
Human genome variation, 2017Co-Authors: Long Guo, Nursel Elcioglu, Zheng Wang, Yasemin K Demirkol, Pinar Isguven, Naomichi Matsumoto, Nishimura, Noriko Miyake, Shiro IkegawaAbstract:Marshall-Stickler syndrome represents a spectrum of inherited connective tissue disorders affecting the ocular, auditory, and skeletal systems. The syndrome is caused by mutations in the COL2A1, COL11A1, COL11A2, COL9A1, and COL9A2 genes. In this study, we examined four Turkish families with Marshall-Stickler syndrome using whole-exome sequencing and identified one COL2A1 mutation and three COL11A1 mutations. Two of the COL11A1 mutations were novel. Our findings expand our knowledge of the COL11A1 mutational spectrum that causes Marshall-Stickler syndrome.
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novel and recurrent col11a1 and col2a1 mutations in the marshall stickler syndrome spectrum
Human genome variation, 2017Co-Authors: Long Guo, Nursel Elcioglu, Zheng Wang, Yasemin K Demirkol, Pinar Isguven, Naomichi Matsumoto, Noriko Miyake, Gen Nishimura, Shiro IkegawaAbstract:Marshall-Stickler syndrome represents a spectrum of inherited connective tissue disorders affecting the ocular, auditory, and skeletal systems. The syndrome is caused by mutations in the COL2A1, COL11A1, COL11A2, COL9A1, and COL9A2 genes. In this study, we examined four Turkish families with Marshall-Stickler syndrome using whole-exome sequencing and identified one COL2A1 mutation and three COL11A1 mutations. Two of the COL11A1 mutations were novel. Our findings expand our knowledge of the COL11A1 mutational spectrum that causes Marshall-Stickler syndrome.
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revisit of multiple epiphyseal dysplasia ethnic difference in genotypes and comparison of radiographic features linked to the comp and matn3 genes
American Journal of Medical Genetics Part A, 2011Co-Authors: Ok Hwa Kim, Sheila Unger, Shiro Ikegawa, Hyun Woong Park, Moon Woo Seong, Tae Joon Cho, Gen Nishimura, Andrea Supertifurga, In Ho Choi, Hae Ryong SongAbstract:Multiple epiphyseal dysplasia (MED) is a genetically heterogeneous group of diseases characterized by variable degrees of epiphyseal abnormality primarily involving the hip and knee joints. The purpose of this study was to investigate the frequency of mutations in individuals with a clinical and radiographic diagnosis of MED and to test the hypothesis that characteristic radiological findings may be helpful in predicting the gene responsible. The radiographs of 74 Korean patients were evaluated by a panel of skeletal dysplasia experts. Six genes known to be associated with MED (COMP, MATN3, COL9A1, COL9A2, COL9A3, and DTDST) were screened by sequencing. Mutations were found in 55 of the 63 patients (87%). MATN3 mutations were found in 30 patients (55%), followed by COMP mutations in 23 (41%), and COL9A2 and DTDST mutations in one patient (2%) each. Comparisons of radiographic findings in patients with COMP and MATN3 mutations showed that albeit marked abnormalities in hip and knee joints were observed in both groups, the degree of involvement and the morphology of dysplastic epiphyses differed markedly. The contour of the pelvic acetabulum, the presence of metaphyseal vertical striations, and/or the brachydactyly of the hand were also found to be highly correlated with the genotypes. The study confirms that MATN3 and COMP are the genes most frequently responsible for MED and that subtle radiographic signs may give precious indications on which gene(s) should be prioritized for mutational screening in a given individual.
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Comprehensive screening of multiple epiphyseal dysplasia mutations in Japanese population.
American journal of medical genetics. Part A, 2006Co-Authors: Taichi Itoh, Nishimura, Shuya Shirahama, Eiji Nakashima, Koichi Maeda, Nobuhiko Haga, Hiroshi Kitoh, Rika Kosaki, Hirofumi Ohashi, Shiro IkegawaAbstract:Multiple epiphyseal dysplasia (MED) is among the most genetically heterogeneous skeletal dysplasias. Six genes involved in MED, COMP, MATN3, COL9A1, COL9A2, COL9A3, and DTDST have been identified; however, the presence of additional disease genes has been reported, and the detection rate for mutations in known genes accounts for no more than 50% of patients with MED in Western populations. Here, we screened the six known disease genes in 35 consecutive Japanese MED patients. We analyzed the entire coding region of each gene, along with flanking intron–exon junctions, by direct sequencing. A total of 19 mutations were identified in COMP, MATN3, COL9A2, COL9A3, and DTDST. The detection rate for known mutations was higher in this study than in previous reports, and we identified a substantially different spectrum of mutations. Mutations in MATN3 were more prevalent among these Japanese patients, whereas no DTDST mutations were detected. Most of the mutations were localized within specific regions of each gene: COMP mutations were found in the calmodulin-like repeat domains; MATN3 mutations in the von Willebrand factor type A domain; and type IX collagen gene mutations occurred in the third collagenous domains. Based on the integration of clinical and genetic information, we propose an algorithm for detecting mutations in Japanese MED patients. Our study further supports the existence of additional MED gene(s). © 2006 Wiley-Liss, Inc.
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Novel COL9A3 mutation in a family with multiple epiphyseal dysplasia.
American journal of medical genetics. Part A, 2005Co-Authors: Eiji Nakashima, Gen Nishimura, Koichi Maeda, Nobuhiko Haga, Hiroshi Kitoh, Rika Kosaki, Hirofumi Ohashi, Akihiko Mabuchi, Shiro IkegawaAbstract:Multiple epiphyseal dysplasia (MED) is a common skeletal dysplasia characterized by mild to moderate short stature, early-onset of osteoarthritis (OA) mainly in the hip and knee joints, and abnormally small and/or irregular epiphyses. MED is clinically and genetically heterogeneous. Six causative genes of MED have been reported, including type IX collagen genes (COL9A1, COL9A2, COL9A3). All the type IX collagen mutations previously reported cause exon skipping that loses the COL3 domain. Here we have identified a novel COL9A3 mutation co-segregating in a three-generation family with MED. The mutation (IVS3 + 5G > A) was speculated to lose the COL3 domain by skipping of exon 3, which was confirmed by in vitro analysis. The patients were of normal height and had minimal complaints with phenotypes being more severe in male patients. The radiographic phenotypes of the patients were relatively milder than those of previously reported cases, and were indistinguishable to common, idiopathic OA.
Mohammad H. Bagheri - One of the best experts on this subject based on the ideXlab platform.
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MRI Phenotyping of COL9A2/Trp2 and COL9A3/Trp3 Alleles in Lumbar Disc Disease: A Case-control Study in South-Western Iranian Population Reveals a Significant Trp3-Disease Association in Males.
Spine, 2016Co-Authors: Mohammad H. Bagheri, Amir P. Honarpisheh, Majid Yavarian, Zahra Alavi, Jenifer Siegelman, Vladimir I. ValtchinovAbstract:STUDY DESIGN A case-control study of the Trp2/3 alleles of COL9A2/3 genes and their correlation with occurrence of Lumbar disc disease (DDD) as phenotyped by magnetic resonance imaging. OBJECTIVE To establish a better understanding of relationship between presence of said alleles and occurrence of DDD in South-Western Iranian population. SUMMARY OF BACKGROUND DATA A number of genetic predisposing factors have been identified in elevating the risk of developing DDD. Specifically, the Trp2 and Trp3 alleles of COL9A2 and COL9A3 genes have been suggested as DDD risk variants. METHODS A total of 108 patients (mean age = 41±11.8 yrs, range = 20-66 yrs) with 57 controls (mean age = 35±10.0 yrs, range = 20-58 yrs) participated in the study. The frequency of G/A polymorphism in COL9A2 gene on location 326 on chromosome 1 and G/A/C/ or T polymorphism in 103 location of COL9A3 gene on chromosome 20 was assessed using a PCR short-primer technique. Outcome measure was defined as presence of DDD on MRI. Odds ratios (OR) and 95% confidence intervals (CI) were used to assess the likelihood of DDD given occurrence of Trp2(3). RESULTS Each allele was present in both patients and controls. The Trp2 allele was positive in 28.5% of individuals (31.5% of patients; 22.8% of controls), OR 1.55 (0.71-3.56). The Trp3 allele, the frequency was 23.6% in all patients (26.9% patients; 17.5% controls), OR 1.72 (0.73-4.33). We observed a 5.8-fold increase in the odds of DDD in males when the Trp3 allele was present, OR 5.83 (1.09-9.98), P = 0.0273. CONCLUSION Both Trp2 and Trp3 alleles occurred more frequently compared with other studied ethnicities. The sampled Iranian population exhibited a similar Trp2 frequency to a Southern Chinese population, and Trp3 occurrence to Finnish and Greek population. We found that male patient were much more likely to develop DDD when Trp 3 was present. LEVEL OF EVIDENCE N/A.
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mri phenotyping of COL9A2 trp2 and col9a3 trp3 alleles in lumbar disc disease a case control study in south western iranian population reveals a significant trp3 disease association in males
Spine, 2016Co-Authors: Mohammad H. Bagheri, Amir P. Honarpisheh, Majid Yavarian, Zahra Alavi, Jenifer Siegelman, Vladimir I. ValtchinovAbstract:STUDY DESIGN A case-control study of the Trp2/3 alleles of COL9A2/3 genes and their correlation with occurrence of Lumbar disc disease (DDD) as phenotyped by magnetic resonance imaging. OBJECTIVE To establish a better understanding of relationship between presence of said alleles and occurrence of DDD in South-Western Iranian population. SUMMARY OF BACKGROUND DATA A number of genetic predisposing factors have been identified in elevating the risk of developing DDD. Specifically, the Trp2 and Trp3 alleles of COL9A2 and COL9A3 genes have been suggested as DDD risk variants. METHODS A total of 108 patients (mean age = 41±11.8 yrs, range = 20-66 yrs) with 57 controls (mean age = 35±10.0 yrs, range = 20-58 yrs) participated in the study. The frequency of G/A polymorphism in COL9A2 gene on location 326 on chromosome 1 and G/A/C/ or T polymorphism in 103 location of COL9A3 gene on chromosome 20 was assessed using a PCR short-primer technique. Outcome measure was defined as presence of DDD on MRI. Odds ratios (OR) and 95% confidence intervals (CI) were used to assess the likelihood of DDD given occurrence of Trp2(3). RESULTS Each allele was present in both patients and controls. The Trp2 allele was positive in 28.5% of individuals (31.5% of patients; 22.8% of controls), OR 1.55 (0.71-3.56). The Trp3 allele, the frequency was 23.6% in all patients (26.9% patients; 17.5% controls), OR 1.72 (0.73-4.33). We observed a 5.8-fold increase in the odds of DDD in males when the Trp3 allele was present, OR 5.83 (1.09-9.98), P = 0.0273. CONCLUSION Both Trp2 and Trp3 alleles occurred more frequently compared with other studied ethnicities. The sampled Iranian population exhibited a similar Trp2 frequency to a Southern Chinese population, and Trp3 occurrence to Finnish and Greek population. We found that male patient were much more likely to develop DDD when Trp 3 was present. LEVEL OF EVIDENCE N/A.
Leena Ala-kokko - One of the best experts on this subject based on the ideXlab platform.
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Intervertebral disc degeneration in relation to the COL9A3 and the IL-1ß gene polymorphisms
European spine journal : official publication of the European Spine Society the European Spinal Deformity Society and the European Section of the Cerv, 2005Co-Authors: Svetlana Solovieva, Leena Ala-kokko, Jaana Lohiniva, Päivi Leino-arjas, Raili Raininko, Katariina Luoma, Hilkka RiihimäkiAbstract:Disc degeneration is a complex condition in which environmental factors and multiple genes are expected to act together to determine the degenerative phenotype. Recently associations of COL9A2 (Trp2 allele) and COL9A3 (Trp3 allele) polymorphisms with lumbar disc disease characterized by sciatica have been reported. However, it is not known whether the Trp2 or Trp3 alleles contribute to disc degeneration (DD). In this study, the association between the collagen genes polymorphisms and lumbar DD was investigated. Furthermore, the influence of the IL-1β(C3954-T) polymorphism on the association of collagen genes polymorphisms with DD was examined. Lumbar intervertebral discs of 135 middle-aged occupationally active men were evaluated with magnetic resonance imaging, using decreased signal intensity of the nucleus pulposus, disc bulges, and decreased disc height as signs of degeneration. Blood samples were analysed for the presence of COL9A3 and COL9A2 tryptophan alleles (Trp3 and Trp2 alleles). The COL11A2, COL2A1 and IL-1β(C3954-T) polymorphisms were also analysed. Multivariate logistic regression analysis allowing for occupation and body mass index showed that the carriage of the Trp3 allele in the absence of the IL-1βT3954 allele increased the risk of dark nucleus pulposus (OR 7.0, 95% CI 1.3–38.8) and joint occurrence of degenerative changes (OR 8.0, 95% CI 1.4–44.7). There was no effect of the Trp3 allele on DD in the presence of the IL-1βT3954 allele. The carriers of the COL11A2 minor allele had an increased risk of disc bulges (OR 2.1, 95% CI 1.0–4.2) as compared with non-carriers. The results suggest that the effect of the COL9A3 gene polymorphism on DD might be modified by the IL-1β gene polymorphism.
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Mutations in the known genes are not the major cause of MED; distinctive phenotypic entities among patients with no identified mutations
European Journal of Human Genetics, 2005Co-Authors: Eveliina Jakkula, Michael D. Briggs, Gail C. Jackson, Outi Mäkitie, William G. Cole, Malwina Czarny-ratacjzak, Rita Damignani, Miki Susic, Leena Ala-kokkoAbstract:Multiple epiphyseal dysplasia (MED) is a clinically and genetically heterogeneous chondrodysplasia. Mutations in six genes ( COMP , COL9A1 , COL9A2 , COL9A3 , MATN3 and DTDST ) have been reported, but the genotype–phenotype correlations and the proportions of cases due to mutations in these genes are still not well characterized. We performed a clinical, radiological and molecular analysis of known MED genes on 29 consecutive MED patients. The mutation analysis resulted in identification of the DTDST mutation in four patients (14%), the COMP mutation in three (10%) and the MATN3 mutation in three (10%). Thus, a disease-causing mutation was identified in 10 patients altogether (34%). The phenotypic features observed in the patients with mutations were in accordance with previously described phenotypes, but two new distinct phenotypic entities were identified in patients in whom no mutation was found. One of them was characterized by severe, early-onset dysplasia of the proximal femurs with almost complete absence of the secondary ossification centres and abnormal development of the femoral necks. The other phenotype was characterized by ‘mini-epiphyses’, resulting in severe dysplasia of the proximal femoral heads. The findings suggest that mutations in the known genes are not the major cause of MED and are responsible for less than half of the cases. The existence of additional MED loci is supported by the exclusion of known loci by mutation analysis and finding of specific subgroups among these patients.
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Sequence variations in the collagen IX and XI genes are associated with degenerative lumbar spinal stenosis
Annals of the rheumatic diseases, 2003Co-Authors: N Noponen-hietala, Jaro Karppinen, Minna Männikkö, E Kyllönen, E Ilkko, Jurg Ott, Leena Ala-kokkoAbstract:Background: Degenerative lumbar spinal stenosis (LSS) is usually caused by disc herniation or degeneration. Several genetic factors have been implicated in disc disease. Tryptophan alleles in COL9A2 and COL9A3 have been shown to be associated with lumbar disc disease in the Finnish population, and polymorphisms in the vitamin D receptor gene (VDR) ( Fok I and Taq I), the matrix metalloproteinase-3 gene (MMP-3) and an aggrecan gene (AGC1) VNTR have been reported to be associated with disc degeneration. In addition, an IVS6-4 a>t polymorphism in COL11A2 has been found in connection with stenosis caused by ossification of the posterior longitudinal ligament in the Japanese population. Objective: To study the role of genetic factors in LSS. Methods: 29 Finnish probands were analysed for mutations in the genes coding for intervertebral disc matrix proteins, COL1A1, COL1A2, COL2A1, COL9A1, COL9A2, COL9A3, COL11A1, COL11A2, and AGC1. VDR and MMP-3 polymorphisms were also analysed. Sequence variations were tested in 56 Finnish controls. Results: Several disease associated alleles were identified. A splice site mutation in COL9A2 leading to a premature translation termination codon and the generation of a truncated protein was identified in one proband, another had the Trp2 allele, and four others the Trp3 allele. The frequency of the COL11A2 IVS6 −4 t allele was 93.1% in the probands and 72.3% in controls (p = 0.0016). The differences in genotype frequencies for this site were less significant (p = 0.0043). Conclusions: Genetic factors have an important role in the pathogenesis of LSS.
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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, Paul Holden, Bernhard Zabel, Ralph S Lachman, David L. Rimoin, 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.
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Splicing mutations in the COL3 domain of collagen IX cause multiple epiphyseal dysplasia.
American journal of medical genetics, 2000Co-Authors: Jaana Lohiniva, Petteri Paassilta, Ulpu Seppänen, Outi Vierimaa, Sirpa Kivirikko, Leena Ala-kokkoAbstract:We report on a three-generation family with multiple epiphyseal dysplasia (MED). The propositus had typical MED findings of knees, ankles, elbows, and hands in childhood. The 2 other affected relatives were adults. The main clinical findings consisted of osteochondritis dissecans and osteoarthritis of the knees. DNA of the propositus was screened for mutations by conformation sensitive gel electrophoresis in all known candidate genes for MED, cartilage oligomeric matrix protein, and the COL9A1, COL9A2, and COL9A3 genes coding for the α1, α2, and α3 chains of collagen IX. The screening identified a unique change in PCR products of exon 3 of the COL9A3 gene. Sequencing indicated a G to A mutation in the acceptor splice site (G−1IVS2A) of intron 2 in all affected relatives, but not in unaffected relatives. Analysis of RNA from the propositus indicated a skipping of exon 3, and thus, a deletion of 12 amino acid recidues as a consequence of the mutation. All four other collagen IX mutations previously described in MED have consequences identical to that characterized here, thus it seems likely that this type of mutation in collagen IX plays an important role in the pathogenesis of MED. Am. J. Med. Genet. 90:216–222, 2000. © 2000 Wiley-Liss, Inc.