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Article: A base substitution at a splice site in the COL3A1 gene causes exon skipping and generates abnormal type III procollagen in a patient with Ehlers-Danlos syndrome type IV

TitleA base substitution at a splice site in the COL3A1 gene causes exon skipping and generates abnormal type III procollagen in a patient with Ehlers-Danlos syndrome type IV
Authors
Issue Date1990
PublisherAmerican Society for Biochemistry and Molecular Biology, Inc. The Journal's web site is located at http://www.jbc.org/
Citation
Journal Of Biological Chemistry, 1990, v. 265 n. 28, p. 17070-17077 How to Cite?
AbstractThe dermis of a child with Ehlers-Danlos syndrome type IV (EDS-IV) contained about 11% of the normal amount of type III collagen and cultured dermal fibroblasts produced a reduced amount of type III procollagen which was secreted poorly. Type III collagen produced by these cells contained normal and abnormal α-chains and cyanogen bromide peptides. The site of the structural defect in the abnormal α1(III) chains was localized to the region of Met797, which is at the junction of the two carboxyl-terminal CB5 and CB9 cyanogen bromide peptides. Chemical cleavage of hetero-duplexes formed between EDS-IV mRNA and a normal cDNA clone covering the CB5 and CB9 region showed that about 100 nucleotides were mismatched. Sequencing of amplified and cloned cDNA spanning the mutant region revealed a 108 nucleotide deletion corresponding to amino acid residues Gly775 to Lys810. The deleted nucleotide sequence corresponded to sequences that, by analogy to the organization of the type I collagen genes, should be precisely encoded by exon 41 of the COL3A1 gene. Sequencing of amplified genomic DNA, prepared using disimilar amounts of primers specific for exons 41 and 42, displayed a base substitution (G-to-A) in the highly conserved GT dinucleotide of the 5' splice site of intron 41. Normal sequences were also obtained from the normal allele. It is likely that the GT-to-AT transition at the splice donor site of intron 41 generated an abnormally spliced mRNA in which sequences of exon 40 and 42 were joined together with maintenance of the reading frame. The corresponding peptide deletion included the cyanogen bromide cleavage site Met797-Pro798 and the mammalian collagenase cleavage site at Gly781-Ile782. These losses account for the resistance of EDS-IV collagen to cyanogen bromide and mammalian collagenase digestion. Cultured fibroblasts produced normal homotrimer, mutant homotrimer, and mixed heterotrimer type III collagen molecules. The mutant homotrimer molecules were the major pepsin-resistant species and about 69% of the α1(III) mRNA was in the mutant form.
Persistent Identifierhttp://hdl.handle.net/10722/147347
ISSN
2015 Impact Factor: 4.258
2015 SCImago Journal Rankings: 3.151
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorCole, WGen_US
dc.contributor.authorChiodo, AAen_US
dc.contributor.authorLamande, SRen_US
dc.contributor.authorJaneczko, Ren_US
dc.contributor.authorRamirez, Fen_US
dc.contributor.authorDahl, HHMen_US
dc.contributor.authorChan, Den_US
dc.contributor.authorBateman, JFen_US
dc.date.accessioned2012-05-29T06:03:05Z-
dc.date.available2012-05-29T06:03:05Z-
dc.date.issued1990en_US
dc.identifier.citationJournal Of Biological Chemistry, 1990, v. 265 n. 28, p. 17070-17077en_US
dc.identifier.issn0021-9258en_US
dc.identifier.urihttp://hdl.handle.net/10722/147347-
dc.description.abstractThe dermis of a child with Ehlers-Danlos syndrome type IV (EDS-IV) contained about 11% of the normal amount of type III collagen and cultured dermal fibroblasts produced a reduced amount of type III procollagen which was secreted poorly. Type III collagen produced by these cells contained normal and abnormal α-chains and cyanogen bromide peptides. The site of the structural defect in the abnormal α1(III) chains was localized to the region of Met797, which is at the junction of the two carboxyl-terminal CB5 and CB9 cyanogen bromide peptides. Chemical cleavage of hetero-duplexes formed between EDS-IV mRNA and a normal cDNA clone covering the CB5 and CB9 region showed that about 100 nucleotides were mismatched. Sequencing of amplified and cloned cDNA spanning the mutant region revealed a 108 nucleotide deletion corresponding to amino acid residues Gly775 to Lys810. The deleted nucleotide sequence corresponded to sequences that, by analogy to the organization of the type I collagen genes, should be precisely encoded by exon 41 of the COL3A1 gene. Sequencing of amplified genomic DNA, prepared using disimilar amounts of primers specific for exons 41 and 42, displayed a base substitution (G-to-A) in the highly conserved GT dinucleotide of the 5' splice site of intron 41. Normal sequences were also obtained from the normal allele. It is likely that the GT-to-AT transition at the splice donor site of intron 41 generated an abnormally spliced mRNA in which sequences of exon 40 and 42 were joined together with maintenance of the reading frame. The corresponding peptide deletion included the cyanogen bromide cleavage site Met797-Pro798 and the mammalian collagenase cleavage site at Gly781-Ile782. These losses account for the resistance of EDS-IV collagen to cyanogen bromide and mammalian collagenase digestion. Cultured fibroblasts produced normal homotrimer, mutant homotrimer, and mixed heterotrimer type III collagen molecules. The mutant homotrimer molecules were the major pepsin-resistant species and about 69% of the α1(III) mRNA was in the mutant form.en_US
dc.languageengen_US
dc.publisherAmerican Society for Biochemistry and Molecular Biology, Inc. The Journal's web site is located at http://www.jbc.org/en_US
dc.relation.ispartofJournal of Biological Chemistryen_US
dc.subject.meshAdenosine Triphosphatases - Metabolismen_US
dc.subject.meshAmino Acid Sequenceen_US
dc.subject.meshBase Sequenceen_US
dc.subject.meshBlotting, Westernen_US
dc.subject.meshCells, Cultureden_US
dc.subject.meshChilden_US
dc.subject.meshCollagen - Genetics - Isolation & Purificationen_US
dc.subject.meshDna Helicasesen_US
dc.subject.meshEhlers-Danlos Syndrome - Genetics - Metabolismen_US
dc.subject.meshExonsen_US
dc.subject.meshFibroblasts - Metabolismen_US
dc.subject.meshHumansen_US
dc.subject.meshMaleen_US
dc.subject.meshMolecular Sequence Dataen_US
dc.subject.meshMutationen_US
dc.subject.meshPeptide Fragments - Isolation & Purificationen_US
dc.subject.meshPeptide Mappingen_US
dc.subject.meshProcollagen - Geneticsen_US
dc.subject.meshRna Splicingen_US
dc.subject.meshRna, Messenger - Geneticsen_US
dc.subject.meshSkin - Metabolismen_US
dc.titleA base substitution at a splice site in the COL3A1 gene causes exon skipping and generates abnormal type III procollagen in a patient with Ehlers-Danlos syndrome type IVen_US
dc.typeArticleen_US
dc.identifier.emailChan, D:chand@hkucc.hku.hken_US
dc.identifier.authorityChan, D=rp00540en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.pmid2145268-
dc.identifier.scopuseid_2-s2.0-0025064558en_US
dc.identifier.volume265en_US
dc.identifier.issue28en_US
dc.identifier.spage17070en_US
dc.identifier.epage17077en_US
dc.identifier.isiWOS:A1990EA85700058-
dc.publisher.placeUnited Statesen_US
dc.identifier.scopusauthoridCole, WG=7201518727en_US
dc.identifier.scopusauthoridChiodo, AA=6601957013en_US
dc.identifier.scopusauthoridLamande, SR=7004500719en_US
dc.identifier.scopusauthoridJaneczko, R=6602594110en_US
dc.identifier.scopusauthoridRamirez, F=7202326091en_US
dc.identifier.scopusauthoridDahl, HHM=7101725390en_US
dc.identifier.scopusauthoridChan, D=7402216545en_US
dc.identifier.scopusauthoridBateman, JF=16135557700en_US

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