Supravalvular aortic stenosis : genetic and molecular dissection of a complex mutation in the elastin gene
We have identified two elastin gene (ELN) mutations located in cis in two related families with supravalvular aortic stenosis (SVAS). These mutations included an in-frame duplication in exon 18 (1034-1057dup) and a single base substitution in exon 26 (1829G-->A) predicted to result in the amino a...
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Veröffentlicht in: | Human genetics 2001-11, Vol.109 (5), p.512-520 |
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description | We have identified two elastin gene (ELN) mutations located in cis in two related families with supravalvular aortic stenosis (SVAS). These mutations included an in-frame duplication in exon 18 (1034-1057dup) and a single base substitution in exon 26 (1829G-->A) predicted to result in the amino acid substitution R610Q. Haplotype analysis in one of the families identified an individual with a recombination between exon 18 and 26 of the elastin gene. This individual was unaffected and carried the exon 18 insertion mutation but not 1829G-->A. Skin fibroblasts were established from this recombinant normal individual and from an affected individual carrying both of the mutations. Reverse transcription/polymerase chain reaction (RT-PCR) analysis indicated that the expression of the mutant allele was reduced to 12%-27% of the normal allele in the affected but not in the unaffected individual. RNA-blot hybridization and immunoprecipitation experiments revealed reduced steady-state elastin mRNA levels and tropoelastin synthesis in the affected individual. RT-PCR analysis of the mRNA rescued by cycloheximide treatment indicated that mutation 1829G-->A created a cryptic donor splice site within exon 26, resulting in the deletion of four nucleotides at the 3'-end of exon 26 and a frameshift in the mRNA. This frameshift mutation generated a premature termination codon in the domain encoded by exon 28, clearly resulting in nonsense-mediated decay (NMD) of this frameshift RNA product. Despite considerable variability in the molecular nature of mutations responsible for SVAS, the unifying mechanism appears to be the generation of null alleles by NMD leading to elastin haploinsufficiency. |
doi_str_mv | 10.1007/s00439-001-0608-z |
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These mutations included an in-frame duplication in exon 18 (1034-1057dup) and a single base substitution in exon 26 (1829G-->A) predicted to result in the amino acid substitution R610Q. Haplotype analysis in one of the families identified an individual with a recombination between exon 18 and 26 of the elastin gene. This individual was unaffected and carried the exon 18 insertion mutation but not 1829G-->A. Skin fibroblasts were established from this recombinant normal individual and from an affected individual carrying both of the mutations. Reverse transcription/polymerase chain reaction (RT-PCR) analysis indicated that the expression of the mutant allele was reduced to 12%-27% of the normal allele in the affected but not in the unaffected individual. RNA-blot hybridization and immunoprecipitation experiments revealed reduced steady-state elastin mRNA levels and tropoelastin synthesis in the affected individual. RT-PCR analysis of the mRNA rescued by cycloheximide treatment indicated that mutation 1829G-->A created a cryptic donor splice site within exon 26, resulting in the deletion of four nucleotides at the 3'-end of exon 26 and a frameshift in the mRNA. This frameshift mutation generated a premature termination codon in the domain encoded by exon 28, clearly resulting in nonsense-mediated decay (NMD) of this frameshift RNA product. Despite considerable variability in the molecular nature of mutations responsible for SVAS, the unifying mechanism appears to be the generation of null alleles by NMD leading to elastin haploinsufficiency.</description><identifier>ISSN: 0340-6717</identifier><identifier>EISSN: 1432-1203</identifier><identifier>DOI: 10.1007/s00439-001-0608-z</identifier><identifier>PMID: 11735026</identifier><identifier>CODEN: HUGEDQ</identifier><language>eng</language><publisher>Heidelberg: Springer</publisher><subject>Alleles ; Amino Acid Sequence ; Aortic Stenosis, Supravalvular - genetics ; Base Sequence ; Biological and medical sciences ; DNA ; DNA Primers ; Elastin - genetics ; Exons ; Female ; Fundamental and applied biological sciences. Psychology ; Gene Frequency ; Humans ; Male ; Molecular and cellular biology ; Molecular Sequence Data ; Mutation, Missense ; Pedigree ; Reverse Transcriptase Polymerase Chain Reaction</subject><ispartof>Human genetics, 2001-11, Vol.109 (5), p.512-520</ispartof><rights>2002 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c393t-6aa7bfa64527c3958b008186576b092a8f7fd85e66f097cc97e8f285e7fd5be53</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=14159142$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/11735026$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>URBAN, Zsolt</creatorcontrib><creatorcontrib>JUN ZHANG</creatorcontrib><creatorcontrib>DAVIS, Elaine C</creatorcontrib><creatorcontrib>MAEDA, Gregg K</creatorcontrib><creatorcontrib>KUMAR, Anil</creatorcontrib><creatorcontrib>STALKER, Heather</creatorcontrib><creatorcontrib>BELMONT, John W</creatorcontrib><creatorcontrib>BOYD, Charles D</creatorcontrib><creatorcontrib>WALLACE, Margaret R</creatorcontrib><title>Supravalvular aortic stenosis : genetic and molecular dissection of a complex mutation in the elastin gene</title><title>Human genetics</title><addtitle>Hum Genet</addtitle><description>We have identified two elastin gene (ELN) mutations located in cis in two related families with supravalvular aortic stenosis (SVAS). These mutations included an in-frame duplication in exon 18 (1034-1057dup) and a single base substitution in exon 26 (1829G-->A) predicted to result in the amino acid substitution R610Q. Haplotype analysis in one of the families identified an individual with a recombination between exon 18 and 26 of the elastin gene. This individual was unaffected and carried the exon 18 insertion mutation but not 1829G-->A. Skin fibroblasts were established from this recombinant normal individual and from an affected individual carrying both of the mutations. Reverse transcription/polymerase chain reaction (RT-PCR) analysis indicated that the expression of the mutant allele was reduced to 12%-27% of the normal allele in the affected but not in the unaffected individual. RNA-blot hybridization and immunoprecipitation experiments revealed reduced steady-state elastin mRNA levels and tropoelastin synthesis in the affected individual. RT-PCR analysis of the mRNA rescued by cycloheximide treatment indicated that mutation 1829G-->A created a cryptic donor splice site within exon 26, resulting in the deletion of four nucleotides at the 3'-end of exon 26 and a frameshift in the mRNA. This frameshift mutation generated a premature termination codon in the domain encoded by exon 28, clearly resulting in nonsense-mediated decay (NMD) of this frameshift RNA product. Despite considerable variability in the molecular nature of mutations responsible for SVAS, the unifying mechanism appears to be the generation of null alleles by NMD leading to elastin haploinsufficiency.</description><subject>Alleles</subject><subject>Amino Acid Sequence</subject><subject>Aortic Stenosis, Supravalvular - genetics</subject><subject>Base Sequence</subject><subject>Biological and medical sciences</subject><subject>DNA</subject><subject>DNA Primers</subject><subject>Elastin - genetics</subject><subject>Exons</subject><subject>Female</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Gene Frequency</subject><subject>Humans</subject><subject>Male</subject><subject>Molecular and cellular biology</subject><subject>Molecular Sequence Data</subject><subject>Mutation, Missense</subject><subject>Pedigree</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><issn>0340-6717</issn><issn>1432-1203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2001</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkU1v1DAQhi1E1S6lP4AL8gVuacd2bCfcUMWXVKkH2rM18dqQyokXT1JBfz3e7ko9zejVM-_hGcbeCbgUAPaKAFrVNwCiAQNd8_SKbUSrZCMkqNdsA6qFxlhhz9gboofK6V7qU3YmhFUapNmwh5_rruAjpsc1YeGYyzJ6TkuYM43EP_FfYQ77COctn3IK_pnbjkTBL2OeeY4cuc_TLoW_fFoXfE7HmS-_Aw8Jaan7vuUtO4mYKFwc5zm7__rl7vp7c3P77cf155vGq14tjUG0Q0TTamlrorsBoBOd0dYM0Evsoo3bTgdjIvTW-96GLsoa1FgPQatz9vHQuyv5zxpocdNIPqSEc8grOSuVAt33FRQH0JdMVEJ0uzJOWP45AW4v2B0EuyrO7QW7p3rz_li-DlPYvlwcjVbgwxFA8phiwdmP9MK19Qeileo_fYOE1w</recordid><startdate>20011101</startdate><enddate>20011101</enddate><creator>URBAN, Zsolt</creator><creator>JUN ZHANG</creator><creator>DAVIS, Elaine C</creator><creator>MAEDA, Gregg K</creator><creator>KUMAR, Anil</creator><creator>STALKER, Heather</creator><creator>BELMONT, John W</creator><creator>BOYD, Charles D</creator><creator>WALLACE, Margaret R</creator><general>Springer</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20011101</creationdate><title>Supravalvular aortic stenosis : genetic and molecular dissection of a complex mutation in the elastin gene</title><author>URBAN, Zsolt ; JUN ZHANG ; DAVIS, Elaine C ; MAEDA, Gregg K ; KUMAR, Anil ; STALKER, Heather ; BELMONT, John W ; BOYD, Charles D ; WALLACE, Margaret R</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c393t-6aa7bfa64527c3958b008186576b092a8f7fd85e66f097cc97e8f285e7fd5be53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2001</creationdate><topic>Alleles</topic><topic>Amino Acid Sequence</topic><topic>Aortic Stenosis, Supravalvular - genetics</topic><topic>Base Sequence</topic><topic>Biological and medical sciences</topic><topic>DNA</topic><topic>DNA Primers</topic><topic>Elastin - genetics</topic><topic>Exons</topic><topic>Female</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Gene Frequency</topic><topic>Humans</topic><topic>Male</topic><topic>Molecular and cellular biology</topic><topic>Molecular Sequence Data</topic><topic>Mutation, Missense</topic><topic>Pedigree</topic><topic>Reverse Transcriptase Polymerase Chain Reaction</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>URBAN, Zsolt</creatorcontrib><creatorcontrib>JUN ZHANG</creatorcontrib><creatorcontrib>DAVIS, Elaine C</creatorcontrib><creatorcontrib>MAEDA, Gregg K</creatorcontrib><creatorcontrib>KUMAR, Anil</creatorcontrib><creatorcontrib>STALKER, Heather</creatorcontrib><creatorcontrib>BELMONT, John W</creatorcontrib><creatorcontrib>BOYD, Charles D</creatorcontrib><creatorcontrib>WALLACE, Margaret R</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Human genetics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>URBAN, Zsolt</au><au>JUN ZHANG</au><au>DAVIS, Elaine C</au><au>MAEDA, Gregg K</au><au>KUMAR, Anil</au><au>STALKER, Heather</au><au>BELMONT, John W</au><au>BOYD, Charles D</au><au>WALLACE, Margaret R</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Supravalvular aortic stenosis : genetic and molecular dissection of a complex mutation in the elastin gene</atitle><jtitle>Human genetics</jtitle><addtitle>Hum Genet</addtitle><date>2001-11-01</date><risdate>2001</risdate><volume>109</volume><issue>5</issue><spage>512</spage><epage>520</epage><pages>512-520</pages><issn>0340-6717</issn><eissn>1432-1203</eissn><coden>HUGEDQ</coden><abstract>We have identified two elastin gene (ELN) mutations located in cis in two related families with supravalvular aortic stenosis (SVAS). These mutations included an in-frame duplication in exon 18 (1034-1057dup) and a single base substitution in exon 26 (1829G-->A) predicted to result in the amino acid substitution R610Q. Haplotype analysis in one of the families identified an individual with a recombination between exon 18 and 26 of the elastin gene. This individual was unaffected and carried the exon 18 insertion mutation but not 1829G-->A. Skin fibroblasts were established from this recombinant normal individual and from an affected individual carrying both of the mutations. Reverse transcription/polymerase chain reaction (RT-PCR) analysis indicated that the expression of the mutant allele was reduced to 12%-27% of the normal allele in the affected but not in the unaffected individual. RNA-blot hybridization and immunoprecipitation experiments revealed reduced steady-state elastin mRNA levels and tropoelastin synthesis in the affected individual. RT-PCR analysis of the mRNA rescued by cycloheximide treatment indicated that mutation 1829G-->A created a cryptic donor splice site within exon 26, resulting in the deletion of four nucleotides at the 3'-end of exon 26 and a frameshift in the mRNA. This frameshift mutation generated a premature termination codon in the domain encoded by exon 28, clearly resulting in nonsense-mediated decay (NMD) of this frameshift RNA product. Despite considerable variability in the molecular nature of mutations responsible for SVAS, the unifying mechanism appears to be the generation of null alleles by NMD leading to elastin haploinsufficiency.</abstract><cop>Heidelberg</cop><cop>Berlin</cop><cop>New York, NY</cop><pub>Springer</pub><pmid>11735026</pmid><doi>10.1007/s00439-001-0608-z</doi><tpages>9</tpages></addata></record> |
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subjects | Alleles Amino Acid Sequence Aortic Stenosis, Supravalvular - genetics Base Sequence Biological and medical sciences DNA DNA Primers Elastin - genetics Exons Female Fundamental and applied biological sciences. Psychology Gene Frequency Humans Male Molecular and cellular biology Molecular Sequence Data Mutation, Missense Pedigree Reverse Transcriptase Polymerase Chain Reaction |
title | Supravalvular aortic stenosis : genetic and molecular dissection of a complex mutation in the elastin gene |
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