Identification of the Molecular Defect in a Family with Spondyloepiphyseal Dysplasia

Lee, Brendan; Vissing, Henrik; Ramirez, Francesco; Rogers, David T.; Rimoin, David L.

doi:10.1126/science.2543071

Cited by 226 publications

(87 citation statements)

References 14 publications

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“…The differentiation into hypertrophic chondrocytes is accompanied with changes in ECM; switching of collagen types from type II to type X and the disappearance of aggrecan and link protein (1,2). Dysfunction of these extracellular macromolecules in mutant mice results in striking skeletal malformation, suggesting their important roles in skeletal formation (3)(4)(5)(6)(7).…”

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confidence: 99%

Mouse Snail Family Transcription Repressors Regulate Chondrocyte, Extracellular Matrix, Type II Collagen, and Aggrecan

Seki

Fujimori

Savagner

et al. 2003

Journal of Biological Chemistry

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Snail family genes are conserved among species during evolution and encode transcription factors expressed at different stages of development in different tissues. These genes are involved in a broad spectrum of biological functions: cell differentiation, cell motility, cell cycle regulation, and apoptosis. However, little is known about the target genes involved in these functions. Here we show that mouse Snail family members, Snail (Sna) and Slug (Slugh), are involved in chondrocyte differentiation by controlling the expression of type II collagen (Col2a1) and aggrecan. In situ hybridization analysis of developing mouse limb demonstrated that Snail and Slug mRNAs were highly expressed in hypertrophic chondrocytes. Inversely, the expression of collagen type II mRNA disappeared during hypertrophic differentiation. Snail and Slug mRNA expression was down-regulated during differentiation of the mouse chondrogenic cell line ATDC5 and overexpression of exogenous Snail or Slug in ATDC5 cells inhibited expression of collagen type II and aggrecan mRNA. Reporter analysis revealed Snail and Slug suppressed the promoter activity of Col2a1, and the E-boxes in the promoter region were the responsible element. Gel shift assay demonstrated the binding of Snail to the E-box. Because type II collagen and aggrecan are major functional components of extracellular matrix in cartilage, these results suggest an important role for Snailrelated transcription repressors during chondrocyte differentiation.During skeletal development, condensed mesenchymal cells give rise to chondrocytes and form cartilage primordia, which serve as templates for endochondral bone formation. In cartilage primordia, chondrocytes undergo further differentiation, starting as proliferating chondrocytes, becoming prehypertrophic chondrocytes and ending as hypertrophic chondrocytes. Chondrocytes secrete abundant extracellular matrix (ECM) 1 into the extracellular space, and the composition of ECM changes during the sequential differentiation steps. Type II collagen and aggrecan are major components of the cartilage extracellular matrix produced by proliferating and prehypertrophic chondrocytes, and type X collagen is a major collagen type produced by hypertrophic chondrocytes. The differentiation into hypertrophic chondrocytes is accompanied with changes in ECM; switching of collagen types from type II to type X and the disappearance of aggrecan and link protein (1, 2

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confidence: 99%

Mouse Snail Family Transcription Repressors Regulate Chondrocyte, Extracellular Matrix, Type II Collagen, and Aggrecan

Seki

Fujimori

Savagner

et al. 2003

Journal of Biological Chemistry

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“…The 7.3-kb and 9.2-kb EcoRI fragments containing portions of the human procollagen al(I1) gene were previously isolated, characterized and subcloned in vector PAT 153 [8,91. M13 UM20 and M13 UM21 obtained from International Biotechnologies, Inc. (New Heaven, CT) were used to subclone the KpnI and BumHI subfragments of the 7.3-kb clone for DNA sequence analysis.…”

Section: Plusmidmentioning

confidence: 99%

“…The human procollagen al(I1) gene has been isolated and characterized using a cosmid clone and a series of overlapping genomic clones [8,91. The entire gene spans six large EcoRI fragments with sizes of 4.8, 7.3, 5.2, 9.2, 3.7 and 4.3 kb in the order of 5' end to 3' end of the gene.…”

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confidence: 99%

Genomic organization of the human procollagen α1 (II) collagen gene

Huang

Seyer

Thompson

et al. 1991

European Journal of Biochemistry

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The nucleotide sequence of the human procollagen a1 (11) collagen gene extending from within the first intron through exon 15, and part of the 15th intron has been determined. This sequence analysis (7056 bases) identifies the intron/exon organization of the region of this gene encoding the N-propeptide and part of the triple-helical domain. Structural comparison of this with the genes of other human fibrillar collagens shows considerable diversity in terms of size and number of introns and exons that encodes the N-propeptide domain. Although the genomic structure of the human procollagen al(I1) gene is quite different from the rat procollagen al(1I) gene, the nucleotide coding sequences are 89% identical.Type I1 collagen is the major structural component of cartilage. It represents a genetically distinct member of fibrillar collagen family and is comprised of three identical aI(11) chains [l -31. Fibrillar procollagens are synthesized in precursor forms containing propeptides at both the amino and carboxyl ends of the molecules. Propeptides are thought to be involved in alignment of the three procollagens chains during triple-helix formation and in their secretion [l -31. Propeptides are cleaved after secretion of the native type I1 collagen molecule [l -31. This process and the coordinated expression of collagen genes are vitally important during vertebrate development [4]. Recently, genetic lesions in the procollagen al(I1) gene have been identified as the basis of several human diseases [5 -81.The human procollagen al(I1) gene has been isolated and characterized using a cosmid clone and a series of overlapping genomic clones [8, 91. The entire gene spans six large EcoRI fragments with sizes of 4.8, 7.3, 5.2, 9.2, 3.7 and 4.3 kb in the order of 5' end to 3' end of the gene. The nucleotide sequence of the 3' region of the gene encoding the C-propeptide has been determined [9]. Recently, overlapping cDNA clones encoding the complete helical region of the human procollagen al(I1) gene were isolated and identified [5]. Analysis of the cDNAs revealed the nucleotide sequence of the mRNA and the deduced amino acid sequence. Exons in the triple-helical and the C-propeptide region of human type I1 collagen are identical in size to exons of the chicken gene [ intronic structure in the triple-helical and the N-propeptide region has not been fully identified [12, 131. In this study, we present genomic nucleotide sequence of 6885 residues of the human procollagen a1 (11) gene encoding the 3' end of the first intron continuously through the 5' end of the 15th intron. This area covers the complete N-propeptide (except exon I) and residues 1-272 of the triple-helical domain of this gene. This information, for the first time, identified the genomic organization of the human type I1 collagen gene. Structural comparison of this gene with other human fibril-forming collagen genes and the rat type I1 collagen gene is presented. MATERIALS AND METHODS PlusmidThe 7.3-kb and 9.2-kb EcoRI fragments containing portions of the human ...

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“…Recent studies have demonstrated that mutations in the COL2Al gene, which encodes the major component of cartilage, cause some rare hereditary cartilage diseases such as spondyloepiphyseal dysplasia and type I1 achondrogenesis-hypochondrogenesis (3)(4)(5)(6). In these disease conditions, abnormality of cartilage is already manifest at an early age.…”

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confidence: 99%

Early‐onset osteoarthritis linked to the type ii procollagen gene. detailed clinical phenotype and further analyses of the gene

Vikkula

Palotie

Ritvaniemi

et al. 1993

Arthritis & Rheumatism

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Objective. To specify in detail the clinical phenotype in 2 Finnish families demonstrating linkage between the type I1 procollagen gene (COL2A1) and osteoarthritis (OA). We also reevaluated the linkage and screened the exon sequences of the COL2Al gene for mutations.Methods. We used single-stranded conformation polymorphism and denaturing gradient-gel electrophoresis techniques for the analyses.Results. Osteoarthritis (OA) is a very common disease which varies in its manifestations. Although most cases are of limited clinical significance, millions of people world-wide become disabled because of OA. Symptoms of pain, stiffness, and limitation of motion are localized to the affected joints. The end result of the process can be grossly deformed joints. The main radiographic features are narrowing of the joint space indicating loss of cartilage, subchondral bone sclerosis, and osteophyte formation in the margins of the bones. The distal interphalangeal joints, hips, knees, the first metatarsophalangeal joints, and the lower lumbar and cervical vertebrae are most commonly affected. Different subsets of the disease can be identified, according to which joints are affected, but the subsets frequently overlap.In some instances, there is an identifiable cause, such as trauma or congenital malformation, but very often, the etiology remains unknown. OA is not an inevitable result of aging; there are elderly people who have no evidence of the disease. Since familial aggregation is seen, genetic factors may be important, particularly in OA of the hand (1,2).

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Identification of the Molecular Defect in a Family with Spondyloepiphyseal Dysplasia

Cited by 226 publications

References 14 publications

Mouse Snail Family Transcription Repressors Regulate Chondrocyte, Extracellular Matrix, Type II Collagen, and Aggrecan

Mouse Snail Family Transcription Repressors Regulate Chondrocyte, Extracellular Matrix, Type II Collagen, and Aggrecan

Genomic organization of the human procollagen α1 (II) collagen gene

Early‐onset osteoarthritis linked to the type ii procollagen gene. detailed clinical phenotype and further analyses of the gene

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