{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T15:07:25Z","timestamp":1791990445558,"version":"4.4.0"},"reference-count":25,"publisher":"BMJ","issue":"4","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J Med Genet"],"published-print":{"date-parts":[[1994,4]]},"abstract":"<jats:p>The features of a 32 year old woman with Ehlers-Danlos syndrome type VIIB and affected members of her family, resulting from a mutation in one COL1A2 allele, were studied. Her dermal type I collagen contained alpha 2(I) chains and mutant pN-alpha 2(I) chains in which the amino-terminal propeptide remained attached to the alpha 2(I) chain. She was heterozygous for an AG--&gt;AC mutation at the splice acceptor site of intron 5 of the COL1A2 gene. The mutation activated a cryptic AG splice acceptor site corresponding to positions +14 and +15 of exon 6 of the COL1A2 gene. In contrast to previous reports only five, rather than all 18, amino acids encoded by exon 6 were deleted in the proband. The deleted peptide removed the amino-proteinase cleavage site, but not the nearby lysine cross linking site in the amino-telopeptide of the alpha 2(I) chain. She was born with bilateral hip dislocations, knee subluxations, and generalised joint hypermobility. Bilateral inguinal herniae and an umbilical hernia were present at birth. Facial features included a depressed nasal bridge with prominent paranasal folds. The skin was soft, moderately hyperelastic, and sagged over the face. Skin fragility and easy bruising were apparent from childhood. Skin wounds healed slowly and with broad, paper thin scars. Throughout her life, she had multiple fractures of the small bones of her hands and feet following moderate trauma. Electron microscopy of the proband's dermis as well as deep fascia and hip joint capsule from her affected brother showed that collagen fibrils in transverse section were nearly circular but with irregular margins. Light microscopy of bone from her affected brother and son showed normal Haversian systems and lamellar bone. All of these tissues contained approximately equal amounts of the normal and mutant alpha2(I) chains. The findings of this study confirm that loss of the amino-proteinase cleavage site of the pro alpha2(I) collagen chains, owing to anomalous splicing of exon 6 sequences in the conversion of pre-mRNA to mRNA, produces the clinical features of Ehlers-Danlos syndrome type VIIB. The history of frequent fractures found in this family is atypical and indicates an overlap with osteogenesis imperfecta.<\/jats:p>","DOI":"10.1136\/jmg.31.4.306","type":"journal-article","created":{"date-parts":[[2008,11,10]],"date-time":"2008-11-10T15:23:16Z","timestamp":1226330596000},"page":"306-311","source":"Crossref","is-referenced-by-count":25,"title":["The clinical features of Ehlers-Danlos syndrome type VIIB resulting from a base substitution at the splice acceptor site of intron 5 of the COL1A2 gene."],"prefix":"10.1136","volume":"31","author":[{"given":"A J","family":"Carr","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A A","family":"Chiodo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J M","family":"Hilton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C W","family":"Chow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A","family":"Hockey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W G","family":"Cole","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[1994,4,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1002\/ajmg.1320290316","article-title":"International nosology of heritable disorders of connective tissue, Berlin 1986","volume":"29","author":"Beighton, P.; DePaepe, A.; Danks, D.","year":"1988","unstructured":"Beighton P, DePaepe A, Danks D, et al. International nosology of heritable disorders of connective tissue, Berlin 1986. Am Med Genet 1988;29:581-94.","journal-title":"Am Med Genet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"5496","DOI":"10.1016\/S0021-9258(19)57243-X","article-title":"Deletion of 24 amino acids from the proal(I) gene of type I procollagen in a patient with the Ehlers Danlos syndrome type","volume":"261","author":"Cole, W.G.; Chan, D.; Chambers, D.W.; Walker, I.D.; Bateman, J.F.","year":"1986","unstructured":"Cole WG, Chan D, Chambers DW, Walker ID, Bateman JF. Deletion of 24 amino acids from the proal(I) gene of type I procollagen in a patient with the Ehlers Danlos syndrome type VII. J Biol Chem 1986;261:5496-503.","journal-title":"VII. J Biol Chem"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/0378-1119(88)90013-3","article-title":"Complete nucleotide sequence of the region encompassing the first twenty-five exons of the human pro-alphal(I) collagen gene (COLlAI)","volume":"67","author":"D'Alessio, M.; Bernard, M.; Pretorius, P.J.; De Wet, W.; Ramirez, F.","year":"1988","unstructured":"D'Alessio M, Bernard M, Pretorius PJ, De Wet W, Ramirez F. Complete nucleotide sequence of the region encompassing the first twenty-five exons of the human pro-alphal(I) collagen gene (COLlAI). Gene 1988;67:105-15.","journal-title":"Gene"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1705","DOI":"10.1002\/j.1460-2075.1989.tb03562.x","article-title":"A base substitution in the exon of a collagen gene causes alternative splicing and generates a structurally abnormal polypeptide in a patient with Ehlers-Danlos syndrome type VII","volume":"8","author":"Weil, D.; D'Alessio, M.; Ramirez, F.","year":"1989","unstructured":"Weil D, D'Alessio M, Ramirez F, et al. A base substitution in the exon of a collagen gene causes alternative splicing and generates a structurally abnormal polypeptide in a patient with Ehlers-Danlos syndrome type VII. EMBOJ 1989;8:1705-10.","journal-title":"EMBOJ"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"16804","DOI":"10.1016\/S0021-9258(19)84777-4","article-title":"Temperaturedependent expression of a collagen splicing defect in the fibroblasts of a patient with Ehlers-Danlos syndrome type","volume":"264","author":"Weil, D.; D'Alessio, M.; Ramirez, F.","year":"1989","unstructured":"Weil D, D'Alessio M, Ramirez F, et al. Temperaturedependent expression of a collagen splicing defect in the fibroblasts of a patient with Ehlers-Danlos syndrome type VII. J Biol Chem 1989;264:16804-9.","journal-title":"VII. 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Jf Biol Chem"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"9093","DOI":"10.1016\/S0021-9258(19)50393-3","article-title":"Ehlers-Danlos syndrome type VII B: incomplete cleavage of abnormal type I procollagen by Nproteinase in vitro results in the formation of copolymers of collagen and partially-cleaved pN collagen that are near circular in cross-section","volume":"267","author":"Watson, R.B.; Wallis, G.A.; Holmes, D.F.; Viljoen, D.; Byers, P.H.; Kadler, K.E.","year":"1992","unstructured":"Watson RB, Wallis GA, Holmes DF, Viljoen D, Byers PH, Kadler KE. Ehlers-Danlos syndrome type VII B: incomplete cleavage of abnormal type I procollagen by Nproteinase in vitro results in the formation of copolymers of collagen and partially-cleaved pN collagen that are near circular in cross-section. i Biol Chem 1992;267:9093-100.","journal-title":"i Biol Chem"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"10006","DOI":"10.1016\/S0021-9258(18)67615-X","article-title":"Defects in the processing of procollagen to collagen are demonstrable in cultured fibroblasts from patients with the Ehlers Danlos and osteogenesis imperfecta syndromes","volume":"261","author":"Minor, R.R.; Sippola-Thiele, M.; McKeon, J.; Berger, J.; Prockop, D.J.","year":"1986","unstructured":"Minor RR, Sippola-Thiele M, McKeon J, Berger J, Prockop DJ. Defects in the processing of procollagen to collagen are demonstrable in cultured fibroblasts from patients with the Ehlers Danlos and osteogenesis imperfecta syndromes. i Biol Chem 1986;261:10006-14.","journal-title":"i Biol Chem"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1007\/BF00204180","article-title":"Ehlers-Danlos syndrome type VII: a single base change that causes exon skipping in the type I collagen a2(I) chain","volume":"87","author":"Nicholls, A.C.; Oliver, J.; Renouf, D.V.; McPheat, J.; Palan, A.; Pope, F.M.","year":"1991","unstructured":"Nicholls AC, Oliver J, Renouf DV, McPheat J, Palan A, Pope FM. Ehlers-Danlos syndrome type VII: a single base change that causes exon skipping in the type I collagen a2(I) chain. Hum Genet 1991;87:193-8.","journal-title":"Hum Genet"},{"key":"ref_10","first-page":"305","article-title":"A mutation in the proa2(I) gene (COL1A2) for type I procollagen in Ehlers-Danlos syndrome type VII: evidence suggesting that skipping of exon 6 in RNA splicing may be a common cause of the phenotype","volume":"48","author":"Vasan, N.S.; Kuivaniemi, H.; Vogel, B.E.","year":"1991","unstructured":"Vasan NS, Kuivaniemi H, Vogel BE, et al. A mutation in the proa2(I) gene (COL1A2) for type I procollagen in Ehlers-Danlos syndrome type VII: evidence suggesting that skipping of exon 6 in RNA splicing may be a common cause of the phenotype. AmJ Hum Genet 1991;48:305-17.","journal-title":"AmJ Hum Genet"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"8561","DOI":"10.1016\/S0021-9258(18)68340-1","article-title":"Identification of a mutation that causes exon skipping during collagen premRNA splicing in an Ehlers-Danlos syndrome variant","volume":"263","author":"Weil, D.; Bernard, M.; Combates, N.","year":"1988","unstructured":"Weil D, Bernard M, Combates N, et al. Identification of a mutation that causes exon skipping during collagen premRNA splicing in an Ehlers-Danlos syndrome variant.J Biol Chem 1988;263:8561-4.","journal-title":"J Biol Chem"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"16007","DOI":"10.1016\/S0021-9258(18)55498-3","article-title":"Structural and functional characterisation of a splicing mutation in the pro-a2(I) collagen gene of an Ehlers-Danlos type VII B patient","volume":"265","year":"1990","unstructured":"Weil D, D'Allessio M, Ramirez F, Eyre DR. Structural and functional characterisation of a splicing mutation in the pro-a2(I) collagen gene of an Ehlers-Danlos type VII B patient. J Biol Chem 1990;265:16007-1 1.","journal-title":"J Biol Chem"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"16376","DOI":"10.1016\/S0021-9258(18)49266-6","article-title":"Ehlers-Danlos syndrome type VIIB. Deletion of 18 amino acids comprising the N-telopeptide region of a proa2(I) chain","volume":"262","author":"Wirtz, M.K.; Glanville, R.W.; Steinmann, B.; Rao, V.; Hollister, D.W.","year":"1987","unstructured":"Wirtz MK, Glanville RW, Steinmann B, Rao V, Hollister DW. Ehlers-Danlos syndrome type VIIB. Deletion of 18 amino acids comprising the N-telopeptide region of a proa2(I) chain. J Biol Chem 1987;262:16376-85.","journal-title":"J Biol Chem"},{"key":"ref_14","first-page":"63619","article-title":"A base substitution at the splice acceptor site of intron 5 of the COL1A2 gene activates a cryptic splice site within exon 6 and generates abnormal type I procollagen in a patient with EhlersDanlos syndrome type VII","volume":"267","author":"Chiodo, A.A.; Hockey, A.; Cole, W.G.","year":"1992","unstructured":"Chiodo AA, Hockey A, Cole WG. A base substitution at the splice acceptor site of intron 5 of the COL1A2 gene activates a cryptic splice site within exon 6 and generates abnormal type I procollagen in a patient with EhlersDanlos syndrome type VII. J Biol Chem 1992;267:63619.","journal-title":"J Biol Chem"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1111\/j.1432-1033.1971.tb01651.x","article-title":"Collagen made of extended a-chains, procollagen, in geneticallydefective dermatosparaxic calves","volume":"23","author":"Lenaers, A.; Ansay, M.; Nusgens, B.V.; Lapiere, C.M.","year":"1971","unstructured":"Lenaers A, Ansay M, Nusgens BV, Lapiere CM. Collagen made of extended a-chains, procollagen, in geneticallydefective dermatosparaxic calves. Eur I Biochem 1971;23:533-43.","journal-title":"Eur I Biochem"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1126\/science.182.4109.298","article-title":"Defective conversion of procollagen to collagen in a form of Ehlers-Danlos syndrome","volume":"182","author":"Lichtenstein, JR, Martin; GR, Kohn; L.D.","year":"1973","unstructured":"Lichtenstein JR, Martin GR, Kohn LD. Defective conversion of procollagen to collagen in a form of Ehlers-Danlos syndrome. Science 1973;182:298-300.","journal-title":"Science"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1038\/jid.1982.3","article-title":"Structural abnormalities in the dermal collagen and elastic matrix from the skin of patients with inherited connective tissue disorders","volume":"79","author":"Holbrook, K.A.; Byers, P.H.","year":"1982","unstructured":"Holbrook KA, Byers PH. Structural abnormalities in the dermal collagen and elastic matrix from the skin of patients with inherited connective tissue disorders. J Invest Dermatol 1982;79(suppl):7-16.","journal-title":"J Invest Dermatol"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1111\/1523-1747.ep12519991","article-title":"Dermatospraxis in a Himalayan cat. I. Biochemical study of dermal collagen","volume":"74","author":"Counts, D.F.; Byers, P.H.; Holbrook, K.A.; Hegreberg, G.A.","year":"1980","unstructured":"Counts DF, Byers PH, Holbrook KA, Hegreberg GA. Dermatospraxis in a Himalayan cat. I. Biochemical study of dermal collagen. J Invest Dermatol 1980;74:96-9.","journal-title":"J Invest Dermatol"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1111\/1523-1747.ep12520000","article-title":"Dermatosparaxis in a Himalayan cat. II. Ultrastructural studies of dermal collagen","volume":"74","author":"Holbrook, K.A.; Byers, P.H.; Counts, D.F.; Hegreberg, G.A.","year":"1980","unstructured":"Holbrook KA, Byers PH, Counts DF, Hegreberg GA. Dermatosparaxis in a Himalayan cat. II. Ultrastructural studies of dermal collagen. J Invest Dermatol 1980;74: 100-4.","journal-title":"J Invest Dermatol"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1002\/path.1711120309","article-title":"Helle 0. A hereditary dysplasia of collagen tissues in sheep","volume":"112","author":"Fjolstad, S.M.","year":"1974","unstructured":"Fjolstad SM, Helle 0. A hereditary dysplasia of collagen tissues in sheep. J Pathol 1974;112:183-8.","journal-title":"J Pathol"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1038\/ng0692-214","article-title":"Evidence for a relationship between Ehlers Danlos type VII C in humans and bovine dermatosparaxis","volume":"1","author":"Nusgens, B.V.; Verellen-Dumoulin, C.; Hermanns-Le, T.","year":"1992","unstructured":"Nusgens BV, Verellen-Dumoulin C, Hermanns-Le T, et al. Evidence for a relationship between Ehlers Danlos type VII C in humans and bovine dermatosparaxis. Nature Genet 1992;1:214-7.","journal-title":"Nature Genet"},{"key":"ref_22","first-page":"235","article-title":"Human dermatospraxis: a form of Ehlers-Danlos syndrome that results from failure to remove the amino-terminal propeptide of type I procollagen","volume":"51","author":"Smith, L.T.; Wertelecki, W.; Milstone, L.M.","year":"1992","unstructured":"Smith LT, Wertelecki W, Milstone LM, et al. Human dermatospraxis: a form of Ehlers-Danlos syndrome that results from failure to remove the amino-terminal propeptide of type I procollagen. Am J Hum Genet 1992;51:235-44.","journal-title":"Am J Hum Genet"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1136\/jmg.24.11.698","article-title":"The clinical features of Ehlers-Danlos syndrome type VII due to a deletion of 24 amino acids from the proa(I) chain of type I procollagen","volume":"24","author":"Cole, W.G.; Evans, R.; Sillence, D.O.","year":"1987","unstructured":"Cole WG, Evans R, Sillence DO. The clinical features of Ehlers-Danlos syndrome type VII due to a deletion of 24 amino acids from the proa(I) chain of type I procollagen. J Med Genet 1987;24:698-701.","journal-title":"J Med Genet"},{"key":"ref_24","first-page":"260","article-title":"A heterozygous collagen defect in a variant of the Ehlers Danlos syndrome type VII. Evidence for a deletion in the proa2(I) chain","author":"Eyre, D.R.; Shapiro, F.D.; Aldridge, J.F.","year":"1985","unstructured":"Eyre DR, Shapiro FD, Aldridge JF. A heterozygous collagen defect in a variant of the Ehlers Danlos syndrome type VII. Evidence for a deletion in the proa2(I) chain. J Biol Chem 1985;260.11322-9.","journal-title":"J Biol Chem"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1172\/JCI110815","article-title":"Abnormal a2-chain in type I collagen from a patient with a form of osteogenesis imperfecta","volume":"71","author":"Byers, P.H.; Shapiro, JR, Rowe; DW, David; KE, Holbrook; K.A.","year":"1983","unstructured":"Byers PH, Shapiro JR, Rowe DW, David KE, Holbrook KA. Abnormal a2-chain in type I collagen from a patient with a form of osteogenesis imperfecta. 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