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Article: Further evidence that the failure to cleave the aminopropeptide of type I procollagen is the cause of Ehlers-Danlos syndrome type VII

TitleFurther evidence that the failure to cleave the aminopropeptide of type I procollagen is the cause of Ehlers-Danlos syndrome type VII
Authors
Issue Date1994
PublisherJohn Wiley & Sons, Inc. The Journal's web site is located at http://www3.interscience.wiley.com/cgi-bin/jhome/38515
Citation
Human Mutation, 1994, v. 3 n. 4, p. 358-364 How to Cite?
AbstractDermal fibroblasts from a Chinese Ehlers-Danlos syndrome type VII patient synthesized approximately equal amounts of normal pro-α2(I) chains of type I procollagen and abnormal ones with electrophoretic mobility of pNα2(I) chains, in which the amino-propeptide (N-propeptide) was retained. Reverse- transcriptase PCR analysis of the proband's RNA showed outsplicing of the 54 base exon 6 in half of the pro-α2(I) mRNAs. Exon 6 encodes 18 amino acids of the N-telopeptide which contains the procollagen N-proteinase cleavage site and a cross-link precursor lysine. Loss of these sequences would result in failure to cleave the amino-propeptide of pro-α2(I) and the accumulation of pN-α2(I) chains. Nucleotide sequencing analyses of the proband's COL1A2 gene showed the presence of a T to C transition at position +2 of intron 6 in one allele and the proband is heterozygous for the defect. This mutation which destroyed the consensus GT dinucleotide at the 5' splice donor site of the intron is responsible for the loss of exon 6 by exon skipping. Electron microscopic analysis of the patient's dermis showed the presence of abnormal collagen I fibrils of irregular diameter and circularity. This mutation in COL1A2 in an EDS VII patient is the first reported case in the Chinese population and is identical to one reported for another EDSVII (Libyan) patient. The occurrence of an identical mutation in two probands of different ethnic origin is direct evidence that the mutant genotype is the cause of the EDS VII phenotype. Therefore the major molecular defect for EDS VIIA/B is outsplicing of exon 6 of either COL1A1 or COL1A2 as a result of single base mutations in the intron-exon junctions. The consequential failure to remove the N-propeptides of either pro-α1(I) or pro-α2(I) is therefore probably the cause of the EDS VII phenotype.
Persistent Identifierhttp://hdl.handle.net/10722/68241
ISSN
2015 Impact Factor: 5.089
2015 SCImago Journal Rankings: 3.670
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorHo, KKYen_HK
dc.contributor.authorKong, RYCen_HK
dc.contributor.authorKuffner, Ten_HK
dc.contributor.authorHsu, LHSen_HK
dc.contributor.authorMa, Len_HK
dc.contributor.authorCheah, KSEen_HK
dc.date.accessioned2010-09-06T06:02:42Z-
dc.date.available2010-09-06T06:02:42Z-
dc.date.issued1994en_HK
dc.identifier.citationHuman Mutation, 1994, v. 3 n. 4, p. 358-364en_HK
dc.identifier.issn1059-7794en_HK
dc.identifier.urihttp://hdl.handle.net/10722/68241-
dc.description.abstractDermal fibroblasts from a Chinese Ehlers-Danlos syndrome type VII patient synthesized approximately equal amounts of normal pro-α2(I) chains of type I procollagen and abnormal ones with electrophoretic mobility of pNα2(I) chains, in which the amino-propeptide (N-propeptide) was retained. Reverse- transcriptase PCR analysis of the proband's RNA showed outsplicing of the 54 base exon 6 in half of the pro-α2(I) mRNAs. Exon 6 encodes 18 amino acids of the N-telopeptide which contains the procollagen N-proteinase cleavage site and a cross-link precursor lysine. Loss of these sequences would result in failure to cleave the amino-propeptide of pro-α2(I) and the accumulation of pN-α2(I) chains. Nucleotide sequencing analyses of the proband's COL1A2 gene showed the presence of a T to C transition at position +2 of intron 6 in one allele and the proband is heterozygous for the defect. This mutation which destroyed the consensus GT dinucleotide at the 5' splice donor site of the intron is responsible for the loss of exon 6 by exon skipping. Electron microscopic analysis of the patient's dermis showed the presence of abnormal collagen I fibrils of irregular diameter and circularity. This mutation in COL1A2 in an EDS VII patient is the first reported case in the Chinese population and is identical to one reported for another EDSVII (Libyan) patient. The occurrence of an identical mutation in two probands of different ethnic origin is direct evidence that the mutant genotype is the cause of the EDS VII phenotype. Therefore the major molecular defect for EDS VIIA/B is outsplicing of exon 6 of either COL1A1 or COL1A2 as a result of single base mutations in the intron-exon junctions. The consequential failure to remove the N-propeptides of either pro-α1(I) or pro-α2(I) is therefore probably the cause of the EDS VII phenotype.en_HK
dc.languageengen_HK
dc.publisherJohn Wiley & Sons, Inc. The Journal's web site is located at http://www3.interscience.wiley.com/cgi-bin/jhome/38515en_HK
dc.relation.ispartofHuman Mutationen_HK
dc.rightsHuman Mutation. Copyright © John Wiley & Sons, Inc.en_HK
dc.subject.meshBase Sequenceen_HK
dc.subject.meshChilden_HK
dc.subject.meshChinaen_HK
dc.subject.meshCollagen - genetics - metabolism - ultrastructureen_HK
dc.subject.meshDNA Mutational Analysisen_HK
dc.subject.meshEhlers-Danlos Syndrome - genetics - metabolismen_HK
dc.subject.meshFemaleen_HK
dc.subject.meshFibroblasts - chemistry - ultrastructureen_HK
dc.subject.meshHumansen_HK
dc.subject.meshMolecular Sequence Dataen_HK
dc.subject.meshPeptide Chain Termination, Translationalen_HK
dc.subject.meshPoint Mutationen_HK
dc.subject.meshPolymerase Chain Reactionen_HK
dc.subject.meshProcollagen - genetics - metabolismen_HK
dc.subject.meshProcollagen N-Endopeptidase - deficiency - genetics - metabolismen_HK
dc.subject.meshRNA Splicing - geneticsen_HK
dc.subject.meshRNA, Messenger - geneticsen_HK
dc.subject.meshSequence Analysis, RNAen_HK
dc.titleFurther evidence that the failure to cleave the aminopropeptide of type I procollagen is the cause of Ehlers-Danlos syndrome type VIIen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=1059-7794&volume=3&spage=358&epage=364&date=1994&atitle=Further+evidence+that+the+failure+to+cleave+the+aminopropeptide+of+type+I+procollagen+is+the+cause+of+Ehlers-Danlos+Syndrome+Type+VIIen_HK
dc.identifier.emailCheah, KSE:hrmbdkc@hku.hken_HK
dc.identifier.authorityCheah, KSE=rp00342en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1002/humu.1380030406en_HK
dc.identifier.pmid8081389-
dc.identifier.scopuseid_2-s2.0-0028247036en_HK
dc.identifier.hkuros1654en_HK
dc.identifier.volume3en_HK
dc.identifier.issue4en_HK
dc.identifier.spage358en_HK
dc.identifier.epage364en_HK
dc.identifier.isiWOS:A1994NT13300005-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridHo, KKY=36819420500en_HK
dc.identifier.scopusauthoridKong, RYC=7005290687en_HK
dc.identifier.scopusauthoridKuffner, T=6603038707en_HK
dc.identifier.scopusauthoridHsu, LHS=36725793300en_HK
dc.identifier.scopusauthoridMa, L=7403574642en_HK
dc.identifier.scopusauthoridCheah, KSE=35387746200en_HK

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