Mutations Near Amino End of α1(I) Collagen Cause Combined Osteogenesis Imperfecta/Ehlers-Danlos Syndrome by Interference with N-propeptide Processing

Abstract

Patients with OI/EDS form a distinct subset of osteogenesis imperfecta (OI) patients. In addition to skeletal fragility, they have characteristics of Ehlers-Danlos syndrome (EDS). We identified 7 children with types III or IV OI, plus severe large and small joint laxity and early progressive scoliosis. In each child with OI/EDS, we identified a mutation in the first 90 residues of the helical region of α1(I) collagen. These mutations prevent or delay removal of the procollagen N-propeptide by purified N-proteinase (ADAMTS-2) in vitro and in pericellular assays. The mutant pN-collagen which results is efficiently incorporated into matrix by cultured fibroblasts and osteoblasts and is prominently present in newly incorporated and immaturely cross-linked collagen. Dermal collagen fibrils have significantly reduced cross-sectional diameters, corroborating incorporation of pN-collagen into fibrils in vivo. Differential scanning calorimetry revealed that these mutant collagens are less stable than the corresponding procollagens, which is not seen with other type I collagen helical mutations. These mutations disrupt a distinct folding region of high thermal stability in the first 90 residues at the amino end of type I collagen and alter the secondary structure of the adjacent N-proteinase cleavage site. Thus, these OI/EDS collagen mutations are directly responsible for the bone fragility of OI and indirectly responsible for EDS symptoms, by interference with N-propeptide removal. Patients with OI/EDS form a distinct subset of osteogenesis imperfecta (OI) patients. In addition to skeletal fragility, they have characteristics of Ehlers-Danlos syndrome (EDS). We identified 7 children with types III or IV OI, plus severe large and small joint laxity and early progressive scoliosis. In each child with OI/EDS, we identified a mutation in the first 90 residues of the helical region of α1(I) collagen. These mutations prevent or delay removal of the procollagen N-propeptide by purified N-proteinase (ADAMTS-2) in vitro and in pericellular assays. The mutant pN-collagen which results is efficiently incorporated into matrix by cultured fibroblasts and osteoblasts and is prominently present in newly incorporated and immaturely cross-linked collagen. Dermal collagen fibrils have significantly reduced cross-sectional diameters, corroborating incorporation of pN-collagen into fibrils in vivo. Differential scanning calorimetry revealed that these mutant collagens are less stable than the corresponding procollagens, which is not seen with other type I collagen helical mutations. These mutations disrupt a distinct folding region of high thermal stability in the first 90 residues at the amino end of type I collagen and alter the secondary structure of the adjacent N-proteinase cleavage site. Thus, these OI/EDS collagen mutations are directly responsible for the bone fragility of OI and indirectly responsible for EDS symptoms, by interference with N-propeptide removal. Osteogenesis imperfecta (OI) 1The abbreviations used are: OI, osteogenesis imperfecta; EDS, Ehlers-Danlos syndrome; DMEM, Dulbecco's modified Eagle's medium; RT, reverse transcriptase. is a genetic disorder of connective tissue characterized by bone fragility, growth deficiency, and blue sclerae (1Sillence D.O. Senn A. Danks D.M. J. Med. Genet. 1979; 16: 101-116Crossref PubMed Scopus (1577) Google Scholar, 2Marini J.C. Behrman R.E. Kliegman R.M. Jenson H.B. Nelson Textbook of Pediatrics. 17th Ed. Saunders, Philadelphia2004: 2336-2338Google Scholar). Defects in type I collagen are well known to cause the full clinical range of OI (3Byers P.H. Cole W.G. Royce P.M. Steinmann B. Connective Tissue and Its Heritable Disorders. 2nd Ed. Wiley-Liss, Inc., New York2002: 385-430Crossref Google Scholar, 4Prockop D.J. Kivirikko K.I. Annu. Rev. Biochem. 1995; 64: 403-434Crossref PubMed Scopus (1379) Google Scholar). Haploinsufficiency for type I collagen, caused by a null α1(I) allele, results in a very mild clinical phenotype (5Willing M.C. Deschenes S.P. Scott D.A. Byers P.H. Slayton R.L. Pitts S.H. Arikat H. Roberts E.J. Am. J. Hum. Genet. 1994; 55: 638-647PubMed Google Scholar). Collagen structural defects, which are usually glycine substitutions or exon skipping defects, have a dominant negative mechanism. They result in a phenotype that ranges from lethal to moderately severe depending on the chain in which the mutation occurs, its location in the chain, and the specific amino acid substituted (6Byers P.H. Wallis G.A. Willing M.C. J. Med. Genet. 1991; 28: 433-442Crossref PubMed Scopus (232) Google Scholar, 7Marini J.C. Lewis M.B. Wang Q. Chen K.J. Orrison B.M. J. Biol. Chem. 1993; 268: 2667-2673Abstract Full Text PDF PubMed Google Scholar). The great majority of mutations causing OI occur in the helical regions of either pro-α1(I) or pro-α2(I). Less than 5% of collagen structural mutations occur in the C-propeptides of the two chains; these mutations cause lethal to moderate OI by delaying chain association into heterotrimer (8Pace J.M. Kuslich C.D. Willing M.C. Byers P.H. J. Med. Genet. 2001; 38: 443-449Crossref PubMed Google Scholar). Ehlers-Danlos VII A and B are also caused by mutations in type I collagen (9Beighton P. De Paepe A. Steinmann B. Tsipouras P. Wenstrup R.J. Am. J. Med. Genet. 1998; 77: 31-37Crossref PubMed Scopus (1373) Google Scholar). These mutations have a well defined location and mechanism of action (10Giunta C. Superti-Furga A. Spranger S. Cole W.G. Steinmann B. J. Bone Joint Surg. Am. 1999; 81: 225-238Crossref PubMed Scopus (62) Google Scholar, 11Cole W.G. Chan D. Chambers G.W. Walker I.D. Bateman J.F. J. Biol. Chem. 1986; 261: 5496-5503Abstract Full Text PDF PubMed Google Scholar, 12D'Alessio M. Ramirez F. Blumberg B.D. Wirtz M.K. Rao V.H. Godfrey M.D. Hollister D.W. Am. J. Hum. Genet. 1991; 49: 400-406PubMed Google Scholar, 13Nicholls A.C. Sher J.L. Wright M.J. Oley C. Mueller R.F. Pope F.M. J. Med. Genet. 2000; 37: E33Crossref PubMed Scopus (19) Google Scholar, 14Byers P.H. Duvic M. Atkinson M. Robinow M. Smith L.T. Krane S.M. Greally M.T. Ludman M. Matalon R. Pauker S. Quanbeck D. Schwarze U. Am. J. Med. Genet. 1997; 72: 94-105Crossref PubMed Scopus (93) Google Scholar, 15Eyre D.R. Shapiro F.D. Aldridge J.F. J. Biol. Chem. 1985; 260: 11322-11329Abstract Full Text PDF PubMed Google Scholar, 16Wirtz M.K. Glanville R.W. Steinmann B. Rao V.H. Hollister D.W. J. Biol. Chem. 1987; 262: 16376-16385Abstract Full Text PDF PubMed Google Scholar, 17Weil D. D'Alessio M. Ramirez F. Steinmann B. Wirtz M.K. Glanville R.W. Hollister D.W. J. Biol. Chem. 1989; 264: 16804-16809Abstract Full Text PDF PubMed Google Scholar, 18Nicholls A.C. Oliver J. Renouf D.V. McPheat J. Palan A. Pope F.M. Hum. Genet. 1991; 87: 193-198Crossref PubMed Scopus (28) Google Scholar, 19Vasan N.S. Kuivaniemi H. Vogel B.E. Minor R.R. Wootton J.A. Tromp G. Weksberg R. Prockop D.J. Am. J. Hum. Genet. 1991; 48: 305-317PubMed Google Scholar, 20Chiodo A.A. Hockey A. Cole W.G. J. Biol. Chem. 1992; 267: 6361-6369Abstract Full Text PDF PubMed Google Scholar, 21Lehmann H.W. Mundlos S. Winterpacht A. Brenner R.E. Zabel B. Muller P.K. Arch. Dermatol. Res. 1994; 286: 425-428Crossref PubMed Scopus (12) Google Scholar, 22Ho K.K. Kong R.Y. Kuffner T. Hsu L.H. Ma L. Cheah K.S. Hum. Mutat. 1994; 3: 358-364Crossref PubMed Scopus (16) Google Scholar). All EDS VII mutations involve a complete or partial loss of exon 6 sequences from either α chain, with EDS VIIA due to mutations in pro-α1(I) and EDS VIIB due to similar mutations in pro-α2(I). Because exon 6 contains both the N-proteinase cleavage site and the interhelix cross-linking lysine, the N-propeptide cannot be cleaved from EDS VII mutant procollagen and cross-linking is defective. Patients with N-propeptide retention have severe generalized joint hypermobility and congenital bilateral hip dislocation. Many have scoliosis because of ligamentous laxity, dislocations of other joints and mild osteopenia, with a few fractures. In those patients in whom dermal fibrils were examined, cross-sectional diameters were normal or decreased and borders were irregular (13Nicholls A.C. Sher J.L. Wright M.J. Oley C. Mueller R.F. Pope F.M. J. Med. Genet. 2000; 37: E33Crossref PubMed Scopus (19) Google Scholar, 14Byers P.H. Duvic M. Atkinson M. Robinow M. Smith L.T. Krane S.M. Greally M.T. Ludman M. Matalon R. Pauker S. Quanbeck D. Schwarze U. Am. J. Med. Genet. 1997; 72: 94-105Crossref PubMed Scopus (93) Google Scholar, 15Eyre D.R. Shapiro F.D. Aldridge J.F. J. Biol. Chem. 1985; 260: 11322-11329Abstract Full Text PDF PubMed Google Scholar, 22Ho K.K. Kong R.Y. Kuffner T. Hsu L.H. Ma L. Cheah K.S. Hum. Mutat. 1994; 3: 358-364Crossref PubMed Scopus (16) Google Scholar, 23Carr A.J. Chiodo A.A. Hilton J.M. Chow C.W. Hockey A. Cole W.G. J. Med. Genet. 1994; 31: 306-311Crossref PubMed Scopus (22) Google Scholar). A small number of mutations at the amino end of the helical region of α2(I) collagen have been noted to cause a combination of EDS and OI symptoms. These mutations include two cases with exon 9 skipping, a case with exon 11 skipping, and a large duplication of E12–32 (24Raff M.L. Craigen W.J. Smith L.T. Keene D.R. Byers P.H. Hum. Genet. 2000; 106: 19-28Crossref PubMed Scopus (29) Google Scholar, 25Nicholls A.C. Oliver J. Renouf D.V. Heath D.A. Pope F.M. Hum. Genet. 1992; PubMed Scopus Google Scholar, S. J. H.W. Muller P.K. S. Hum. Mutat. 1997; Google Scholar, M. S. Prockop D.J. J. Biol. Chem. Full Text PDF PubMed Google Scholar, Vogel B.E. Prockop D.J. 1989; 28: PubMed Scopus Google Scholar). The of EDS in the clinical of these patients. All have bilateral hip dislocations and laxity of large joint dislocations and (24Raff M.L. Craigen W.J. Smith L.T. Keene D.R. Byers P.H. Hum. Genet. 2000; 106: 19-28Crossref PubMed Scopus (29) Google Scholar, S. J. H.W. Muller P.K. S. Hum. Mutat. 1997; Google and scoliosis M. S. Prockop D.J. J. Biol. Chem. Full Text PDF PubMed Google Scholar). In the case with duplication of the dermal that of a (24Raff M.L. Craigen W.J. Smith L.T. Keene D.R. Byers P.H. Hum. Genet. 2000; 106: 19-28Crossref PubMed Scopus (29) Google Scholar). OI in these cases were All blue two imperfecta (24Raff M.L. Craigen W.J. Smith L.T. Keene D.R. Byers P.H. Hum. Genet. 2000; 106: 19-28Crossref PubMed Scopus (29) Google Scholar, M. S. Prockop D.J. J. Biol. Chem. Full Text PDF PubMed Google Scholar, Vogel B.E. Prockop D.J. 1989; 28: PubMed Scopus Google and M. S. Prockop D.J. J. Biol. Chem. Full Text PDF PubMed Google Scholar, Vogel B.E. Prockop D.J. 1989; 28: PubMed Scopus Google Scholar). the child with duplication of E12–32 a We a of patients with mutations in the α1(I) chain have a distinct OI/EDS in which the of OI are and the EDS less severe than in the OI/EDS mutations in The α1(I) OI/EDS mutation is in a high stability folding region at the amino end of the type I collagen These mutations with removal of the the N-proteinase site in exon 6 is Thus, OI/EDS and EDS VII are to have a mechanism for EDS symptoms. were from dermal were cultured in Dulbecco's modified Eagle's and in the of 5% were from bone the of and Tissue 1985; 37: PubMed Scopus Google Scholar). In osteoblasts were from bone by for at with in and in DMEM, and in the of Collagen procollagens, of and were for in by with of in for were from and and with collagens were by of procollagen J. R.E. J. Byers P.H. J. Biol. Chem. 1985; 260: Full Text PDF PubMed Google Scholar). from cultured fibroblasts of and to the P. Biochem. 1987; PubMed Scopus Google Scholar). The region of the α1(I) collagen corresponding to by reverse chain S. R. PubMed Scopus Google Scholar). reverse with of to of the in exon The used a for with a corresponding to of and in exon used of and were for of at at and at and 7 at were directly on a to the of by fibroblasts by from and with of for and the with and from were at a A.C. Oliver J. Renouf D.V. Heath D.A. Pope F.M. Hum. Genet. 1992; PubMed Scopus Google Scholar). procollagen from fibroblasts were with and on and fibroblasts and osteoblasts were to and other for 11 or 9 with and were for with of in and were with collagens were at J.F. Biol. 1994; PubMed Scopus Google Scholar). In newly collagens were for with and from matrix by and with with were from the matrix for with acid and with with were by for and with All were on of Dermal dermal from each and from a for and The were in and with by with the tissue with were with on and with The were in a and were of and fibroblasts were to at and with and to the used in calorimetry and N-propeptide at for and with and to were to the and by addition of to a of and at by at for Differential from to were at and in a prevent of collagen, in were The in on the of and the corresponding not on the scanning of to S. U. S. A. PubMed Scopus Google Scholar). N-proteinase procollagen were in by of and and into A. M. A. S. J.C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). by and to of procollagens, by and by were that two be by in the N-proteinase (ADAMTS-2) purified from A. A. B. J. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google and in in at to each collagen on for of of of were at to partial of structural were at the the of the with with and The were and by on The were on for each were with the of and of were of OI/EDS in have a distinct OI/EDS phenotype All first to for of osteogenesis All have types III or IV OI, with of the children with and bone to range from to All have the of OI and a that ranges from to of the for of the in OI, have significantly than All have blue characteristics of OI/EDS for which the is at the for bone at the are on a from to of joint ranges from to of the to the of the each of the each of the each of the each of the with that of the on the of scoliosis on to to to to 7 with The first the in A with and in the to the is for which the is at the to to to to for bone at the are on a from to of joint ranges from to of the to the of the each of the each of the each of the each of the with that of the on the of scoliosis on with The first the in A with and in the to the is in a The of EDS are severe than the mild to moderate joint in In addition to of large and small joints these have laxity of results in early scoliosis The scoliosis is progressive and to been by the Collagen and the have osteogenesis we the type I collagen by dermal fibroblasts on and collagen not have be with the well known of type I collagen seen in OI a in both and α2(I) and a in the α2(I) from the The normal collagen results to these patients for collagen mutations at the amino end of the helical region of either α1(I) or which not be to cause of of both α revealed that 7 mutations in of causing structural in the 90 residues at the amino end of the α1(I) a mutation A that skipping of exon 7 from the mutant The seen on is the of normal α2(I) chain of a mutant α1(I) The 6 are for glycine at and The the collagen to the amino end of the α2(I) chain to the seen on the α2(I) of the were from both α1(I) and α2(I) in the a mutation or of a with in and mutations causing OI/EDS with in vitro of the N-propeptide of procollagen by purified N-proteinase the of the N-proteinase cleavage site in exon 6 is in Because of association of procollagen patients and of procollagen and mutant pro-α1(I) for mutations in exon 7 and of pro-α1(I) were in these mutations prevent of the N-propeptide from that or two of the mutant pro-α1(I) chain, and the of with two normal pro-α1(I) be The with mutations in and that with or two normal pro-α1(I) were the of two mutant not be The procollagen the at a reduced with normal to the cleavage at and complete in vitro cleavage with normal We also the of procollagen to collagen by the pericellular in a by the of a of to collagen not The procollagen by of the OI/EDS to collagen by the pericellular with the in vitro In with of normal amino is in and 7 to a in and and in 6 and 7 11 pN-collagen in in and pN-collagen present in the of cultured fibroblasts and osteoblasts is incorporated into the matrix by those In each we a of pN-collagen in these with mutations in exon 7 and the of is to the of α1(I) mutations in exon and in is of the of from the amino end of the collagen and have less in the glycine mutations the first 90 residues of the chain, at and not have of pN-collagen than is that the of pN-collagen is in the matrix by cultured osteoblasts than fibroblasts in the for whom osteoblasts were and the very pN-collagen in of α1(I) in form in The matrix also that pN-collagen is efficiently cross-linked into than in the of Dermal pN-collagen into in dermal fibrils from patients with EDS the incorporation of pN-collagen into the been to result in the of the Steinmann B. J. Biol. Chem. 1993; 268: Full Text PDF PubMed Google by of dermal in OI/EDS that pN-collagen is incorporated into OI/EDS matrix in vivo. The diameters of the dermal fibrils of the OI/EDS are significantly than those of fibrils and In the fibrils have the of The fibrils with mutant collagen are to normal are significantly few were seen in OI/EDS the borders of fibrils were the irregular seen in EDS diameters of α1(I) OI/EDS and of fibrils for each and in a of a scanning calorimetry into the structural of for procollagen and collagen are in for the and two type IV OI mutations and which not result in N-propeptide retention or cause EDS symptoms. The of normal procollagen and collagen each have a of in the helical region of collagen result in or two with reduced of with and two mutant in addition to the normal for with mutant of specific for each procollagen and the corresponding collagen are usually because the not to stability of normal and mutant In the of the OI/EDS is with procollagen and collagen that from each a procollagen in and into normal and reduced stability collagen the reduced stability procollagen in and to in in the collagen of and the of procollagen and collagen have a in the of the and normal stability in thermal stability with and N-propeptide that mutations in the first 90 residues at the amino end of the collagen disrupt a distinct folding region that the collagen A and The of the N-propeptide in these mutant for the loss of helical in procollagen that is stable than collagen. The region is by a region mutations the first 90 residues have normal not disrupt the and not N-propeptide The of patients a region at the amino end of the α1(I) collagen chain in which mutations cause a distinct OI/EDS We that mutations in region with of the N-propeptide of type I collagen the N-proteinase cleavage site is in both pericellular and in vitro with purified procollagen and In mutations to the amino end in exon 7 N-propeptide cleavage from of procollagen those or two mutant from the N-proteinase site N-propeptide cleavage from to of two mutant The OI/EDS mutation at the end of exon 11 the of removal. We that the pN-collagen is incorporated into matrix by cultured fibroblasts and osteoblasts of the The of pN-collagen seen in the matrix by fibroblasts is with the in vitro mutations with of a of the α1(I) have a of in matrix than mutations with a delay in have pN-collagen than the corresponding is seen in the case of in which at of α1(I) is in the and very pN-collagen is seen in the and the of N-proteinase in bone than tissue A. Prockop D.J. U. S. A. 1997; PubMed Scopus Google Scholar). also the of than collagen H. A. A. L. J.C. Hum. Mutat. 1998; PubMed Scopus Google and the cleavage of the cleavage site that is known to occur with collagen in the of a collagen structural mutation A. Wootton J.A. Minor R.R. Prockop D.J. J. Biol. Chem. 1992; 267: Full Text PDF PubMed Google Scholar). We also present of pN-collagen incorporation into fibrils in vivo. The dermal fibrils of have a than those of is similar to the in fibrils of EDS VIIA and patients are known to have pN-collagen in fibrils (13Nicholls A.C. Sher J.L. Wright M.J. Oley C. Mueller R.F. Pope F.M. J. Med. Genet. 2000; 37: E33Crossref PubMed Scopus (19) Google Scholar, 14Byers P.H. Duvic M. Atkinson M. Robinow M. Smith L.T. Krane S.M. Greally M.T. Ludman M. Matalon R. Pauker S. Quanbeck D. Schwarze U. Am. J. Med. Genet. 1997; 72: 94-105Crossref PubMed Scopus (93) Google Scholar, 15Eyre D.R. Shapiro F.D. Aldridge J.F. J. Biol. Chem. 1985; 260: 11322-11329Abstract Full Text PDF PubMed Google Scholar, 22Ho K.K. Kong R.Y. Kuffner T. Hsu L.H. Ma L. Cheah K.S. Hum. Mutat. 1994; 3: 358-364Crossref PubMed Scopus (16) Google Scholar, 23Carr A.J. Chiodo A.A. Hilton J.M. Chow C.W. Hockey A. Cole W.G. J. Med. Genet. 1994; 31: 306-311Crossref PubMed Scopus (22) Google the α1(I) OI/EDS not have fibrils with irregular The OI/EDS region a structural of collagen amino acid that the first residues form a stable region that the for the amino end of the collagen its is by a region of residues or and a site D.J. S. J. Biol. PubMed Scopus Google Scholar). The that mutations in the first 90 amino disrupt the region by the end of the and cause structural that into the These structural are a distinct of They are for mutations to the amino end of the and mutations the We not similar for and well other glycine substitutions the first 90 residues not matrix and were for type I collagen helical mutations causing the region of structural caused by mutations into the Thus, the mutations that are responsible for OI/EDS phenotype both and collagen structural they are directly responsible for the OI of the with N-propeptide they are indirectly responsible for the EDS by a mechanism similar to EDS VIIA and In EDS VIIA and the retention of the N-propeptide is caused by a of the N-proteinase cleavage site. In OI/EDS, the cleavage site is to cleavage be on of the region at the amino end of the into the of the N-proteinase site helical J. Prockop D.J. J. Biol. Chem. 1985; 260: Full Text PDF PubMed Google Scholar, L. Kivirikko K.I. Prockop D.J. PubMed Scopus Google Scholar, T. L. Prockop D.J. PubMed Scopus Google and of the normal of the site with acid the α in which cleavage Prockop D.J. J. Biol. Chem. Full Text PDF PubMed Google Scholar). the of the N-propeptide the thermal stability by the N-proteinase cleavage site be in in the OI/EDS is a normal procollagen in which the N-propeptide is the end of the helical region A. 1979; Scopus Google Scholar, A. 1987; PubMed Scopus Google Scholar, A. G. Scott 1989; 28: PubMed Scopus Google Scholar). of the N-proteinase cleavage site not on the normal of the N-propeptide with OI/EDS mutations in α1(I) have a distinct with joint and early progressive well type III and IV OI symptoms, and blue the α1(I) OI/EDS those with exon 7 mutations have N-propeptide severe EDS, and mild to moderate OI, those with exon 11 mutations have less N-propeptide EDS, and severe is that the OI/EDS of these patients are from the clinical of mutations at the amino end of the α2(I) The patients with mutations in α2(I) have a that is similar to EDS VIIA and with severe of large and small joints and bilateral congenital hip (24Raff M.L. Craigen W.J. Smith L.T. Keene D.R. Byers P.H. Hum. Genet. 2000; 106: 19-28Crossref PubMed Scopus (29) Google Scholar, 25Nicholls A.C. Oliver J. Renouf D.V. Heath D.A. Pope F.M. Hum. Genet. 1992; PubMed Scopus Google Scholar, S. J. H.W. Muller P.K. S. Hum. Mutat. 1997; Google Scholar, M. S. Prockop D.J. J. Biol. Chem. Full Text PDF PubMed Google Scholar, Vogel B.E. Prockop D.J. 1989; 28: PubMed Scopus Google Scholar). They have mild of OI, to and blue The in phenotype EDS OI/EDS and α1(I) OI/EDS that is a at the of the collagen or the is to that the mutations of the two are of The EDS and α2(I) OI/EDS cases involve or partial loss of exon or a large result in a of of the mutant chain with to the two of the collagen and cause a similar secondary at the of and The α1(I) OI/EDS cases are glycine substitutions that cause not be to the of the in a with to each that to the in phenotype are the location of the in the fibrils and to cleavage by tissue and Steinmann B. J. Biol. Chem. 1993; 268: Full Text PDF PubMed Google used scanning to that in EDS VIIB fibrils were in a and were in both and on the of collagen and pN-collagen a with in the a on the In the EDS VII fibrils with irregular are in and in the both collagen and Wallis G.A. D. Byers P.H. J. Biol. Chem. 1992; 267: Full Text PDF PubMed Google that fibrils be to by fibrils In EDS VIIA and and α2(I) OI/EDS, the of and in fibrils is with the of on the in a In α1(I) OI/EDS in the is very because by The be in the pN-collagen at the have been cleaved by tissue The α1(I) from α1(I) OI/EDS from those of EDS VIIA in both in that the amino acid residues by exon 6 are in EDS and in secondary structure These for the cleavage of OI/EDS α1(I) the of of by the in exon 6 to the phenotype by to of the structure and location of the N-propeptide in α1(I) α2(I) OI/EDS fibrils and its on tissue into J. C. M. and A. D. L. and of the of of for of joint laxity and scoliosis in We are to the patients and and for and of OI We and Prockop for of the mutation and the mutation at of the with the mutation and