Analysis of mRNA transcripts improves the success rate of molecular genetic testing in OTC deficiency
Background: Ornithine transcarbamylase (OTC) deficiency is the most common inborn error of urea metabolism that can lead to hyperammonemic crises and orotic aciduria. To date, a total of 341 causative mutations within the OTC gene have been described. However, in about 20% of the patients with enzym...
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| Veröffentlicht in: | Molecular genetics and metabolism 2008-07, Vol.94 (3), p.292-297 |
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| container_title | Molecular genetics and metabolism |
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| creator | Engel, Katharina Nuoffer, Jean-Marc Mühlhausen, Chris Klaus, Vera Largiadèr, Carlo R. Tsiakas, Konstantinos Santer, René Wermuth, Bendicht Häberle, Johannes |
| description | Background: Ornithine transcarbamylase (OTC) deficiency is the most common inborn error of urea metabolism that can lead to hyperammonemic crises and orotic aciduria. To date, a total of 341 causative mutations within the OTC gene have been described. However, in about 20% of the patients with enzymatically confirmed OTC deficiency no mutation can be detected when sequencing of genomic DNA analyzing exons and adjacent intronic segments of the OTC gene is performed. Methods: Standard genomic DNA analysis of the OTC gene in five consecutive patients from five families revealed no mutation. Hence, liver tissue was obtained by needle sampling or open biopsy and RNA extracted from liver was analyzed. Results: Complex rearrangements of the OTC transcript (three insertions and two deletions) were found in all five patients. Conclusion: In patients with a strong suspicion of OTC deficiency despite normal results of sequencing exonic regions of the OTC gene, characterization of liver OTC mRNA is highly effective in resolving the genotype. Liver tissue sampling by needle aspiration allows for both enzymatic analysis and RNA based diagnostics of OTC deficiency. |
| doi_str_mv | 10.1016/j.ymgme.2008.03.009 |
| format | Article |
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To date, a total of 341 causative mutations within the OTC gene have been described. However, in about 20% of the patients with enzymatically confirmed OTC deficiency no mutation can be detected when sequencing of genomic DNA analyzing exons and adjacent intronic segments of the OTC gene is performed. Methods: Standard genomic DNA analysis of the OTC gene in five consecutive patients from five families revealed no mutation. Hence, liver tissue was obtained by needle sampling or open biopsy and RNA extracted from liver was analyzed. Results: Complex rearrangements of the OTC transcript (three insertions and two deletions) were found in all five patients. Conclusion: In patients with a strong suspicion of OTC deficiency despite normal results of sequencing exonic regions of the OTC gene, characterization of liver OTC mRNA is highly effective in resolving the genotype. Liver tissue sampling by needle aspiration allows for both enzymatic analysis and RNA based diagnostics of OTC deficiency.</description><identifier>ISSN: 1096-7192</identifier><identifier>EISSN: 1096-7206</identifier><identifier>DOI: 10.1016/j.ymgme.2008.03.009</identifier><identifier>PMID: 18440262</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Base Sequence ; Child, Preschool ; DNA Mutational Analysis ; Female ; Genetic Testing - methods ; Humans ; Infant ; Infant, Newborn ; Liver biopsy ; Male ; mRNA analysis ; Neonatal Screening - methods ; Ornithine Carbamoyltransferase - analysis ; Ornithine Carbamoyltransferase - genetics ; Ornithine Carbamoyltransferase Deficiency Disease - diagnosis ; Ornithine Carbamoyltransferase Deficiency Disease - genetics ; Ornithine transcarbamylase ; RNA, Messenger - analysis ; Sensitivity and Specificity ; Urea cycle defect</subject><ispartof>Molecular genetics and metabolism, 2008-07, Vol.94 (3), p.292-297</ispartof><rights>2008 Elsevier Inc.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c455t-8b3180b49307918fce77cd3e71c72aa00d173f6bdd05eea499720d448ffcc3a53</citedby><cites>FETCH-LOGICAL-c455t-8b3180b49307918fce77cd3e71c72aa00d173f6bdd05eea499720d448ffcc3a53</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S1096719208000747$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18440262$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Engel, Katharina</creatorcontrib><creatorcontrib>Nuoffer, Jean-Marc</creatorcontrib><creatorcontrib>Mühlhausen, Chris</creatorcontrib><creatorcontrib>Klaus, Vera</creatorcontrib><creatorcontrib>Largiadèr, Carlo R.</creatorcontrib><creatorcontrib>Tsiakas, Konstantinos</creatorcontrib><creatorcontrib>Santer, René</creatorcontrib><creatorcontrib>Wermuth, Bendicht</creatorcontrib><creatorcontrib>Häberle, Johannes</creatorcontrib><title>Analysis of mRNA transcripts improves the success rate of molecular genetic testing in OTC deficiency</title><title>Molecular genetics and metabolism</title><addtitle>Mol Genet Metab</addtitle><description>Background: Ornithine transcarbamylase (OTC) deficiency is the most common inborn error of urea metabolism that can lead to hyperammonemic crises and orotic aciduria. To date, a total of 341 causative mutations within the OTC gene have been described. However, in about 20% of the patients with enzymatically confirmed OTC deficiency no mutation can be detected when sequencing of genomic DNA analyzing exons and adjacent intronic segments of the OTC gene is performed. Methods: Standard genomic DNA analysis of the OTC gene in five consecutive patients from five families revealed no mutation. Hence, liver tissue was obtained by needle sampling or open biopsy and RNA extracted from liver was analyzed. Results: Complex rearrangements of the OTC transcript (three insertions and two deletions) were found in all five patients. Conclusion: In patients with a strong suspicion of OTC deficiency despite normal results of sequencing exonic regions of the OTC gene, characterization of liver OTC mRNA is highly effective in resolving the genotype. Liver tissue sampling by needle aspiration allows for both enzymatic analysis and RNA based diagnostics of OTC deficiency.</description><subject>Base Sequence</subject><subject>Child, Preschool</subject><subject>DNA Mutational Analysis</subject><subject>Female</subject><subject>Genetic Testing - methods</subject><subject>Humans</subject><subject>Infant</subject><subject>Infant, Newborn</subject><subject>Liver biopsy</subject><subject>Male</subject><subject>mRNA analysis</subject><subject>Neonatal Screening - methods</subject><subject>Ornithine Carbamoyltransferase - analysis</subject><subject>Ornithine Carbamoyltransferase - genetics</subject><subject>Ornithine Carbamoyltransferase Deficiency Disease - diagnosis</subject><subject>Ornithine Carbamoyltransferase Deficiency Disease - genetics</subject><subject>Ornithine transcarbamylase</subject><subject>RNA, Messenger - analysis</subject><subject>Sensitivity and Specificity</subject><subject>Urea cycle defect</subject><issn>1096-7192</issn><issn>1096-7206</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kcuOEzEQRS0EYoaBL0BCXsEqTbndbbcXLKKIlzRiJDSsLceuDo76EVzukfL3eJIgdrOqWpxbj3sZeyugEiDUx311HHcjVjVAV4GsAMwzdi3AqJWuQT3_1wtTX7FXRHsAIVrTvGRXomsaqFV9zXA9ueFIkfjc8_HnjzXPyU3kUzxk4nE8pPkBieffyGnxHol4chlP9DygXwaX-A4nzNHzjJTjtONx4nf3Gx6wjz7i5I-v2YveDYRvLvWG_fry-X7zbXV79_X7Zn278k3b5lW3laKDbWMkaCO63qPWPkjUwuvaOYAgtOzVNgRoEV1jTHk0NE3X995L18ob9uE8t5z9ZynX2DGSx2FwE84L2U6B1Np0spDvnySVqYVSUhVQnkGfZqKEvT2kOLp0tALsYw52b0852MccLEhbciiqd5fxy3bE8F9zMb4An84AFjseIiZLJ6swxIQ-2zDHJxf8BRMcmw4</recordid><startdate>200807</startdate><enddate>200807</enddate><creator>Engel, Katharina</creator><creator>Nuoffer, Jean-Marc</creator><creator>Mühlhausen, Chris</creator><creator>Klaus, Vera</creator><creator>Largiadèr, Carlo R.</creator><creator>Tsiakas, Konstantinos</creator><creator>Santer, René</creator><creator>Wermuth, Bendicht</creator><creator>Häberle, Johannes</creator><general>Elsevier Inc</general><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><scope>7TM</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope></search><sort><creationdate>200807</creationdate><title>Analysis of mRNA transcripts improves the success rate of molecular genetic testing in OTC deficiency</title><author>Engel, Katharina ; Nuoffer, Jean-Marc ; Mühlhausen, Chris ; Klaus, Vera ; Largiadèr, Carlo R. ; Tsiakas, Konstantinos ; Santer, René ; Wermuth, Bendicht ; Häberle, Johannes</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c455t-8b3180b49307918fce77cd3e71c72aa00d173f6bdd05eea499720d448ffcc3a53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Base Sequence</topic><topic>Child, Preschool</topic><topic>DNA Mutational Analysis</topic><topic>Female</topic><topic>Genetic Testing - methods</topic><topic>Humans</topic><topic>Infant</topic><topic>Infant, Newborn</topic><topic>Liver biopsy</topic><topic>Male</topic><topic>mRNA analysis</topic><topic>Neonatal Screening - methods</topic><topic>Ornithine Carbamoyltransferase - analysis</topic><topic>Ornithine Carbamoyltransferase - genetics</topic><topic>Ornithine Carbamoyltransferase Deficiency Disease - diagnosis</topic><topic>Ornithine Carbamoyltransferase Deficiency Disease - genetics</topic><topic>Ornithine transcarbamylase</topic><topic>RNA, Messenger - analysis</topic><topic>Sensitivity and Specificity</topic><topic>Urea cycle defect</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Engel, Katharina</creatorcontrib><creatorcontrib>Nuoffer, Jean-Marc</creatorcontrib><creatorcontrib>Mühlhausen, Chris</creatorcontrib><creatorcontrib>Klaus, Vera</creatorcontrib><creatorcontrib>Largiadèr, Carlo R.</creatorcontrib><creatorcontrib>Tsiakas, Konstantinos</creatorcontrib><creatorcontrib>Santer, René</creatorcontrib><creatorcontrib>Wermuth, Bendicht</creatorcontrib><creatorcontrib>Häberle, Johannes</creatorcontrib><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><collection>Nucleic Acids Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><jtitle>Molecular genetics and metabolism</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Engel, Katharina</au><au>Nuoffer, Jean-Marc</au><au>Mühlhausen, Chris</au><au>Klaus, Vera</au><au>Largiadèr, Carlo R.</au><au>Tsiakas, Konstantinos</au><au>Santer, René</au><au>Wermuth, Bendicht</au><au>Häberle, Johannes</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Analysis of mRNA transcripts improves the success rate of molecular genetic testing in OTC deficiency</atitle><jtitle>Molecular genetics and metabolism</jtitle><addtitle>Mol Genet Metab</addtitle><date>2008-07</date><risdate>2008</risdate><volume>94</volume><issue>3</issue><spage>292</spage><epage>297</epage><pages>292-297</pages><issn>1096-7192</issn><eissn>1096-7206</eissn><abstract>Background: Ornithine transcarbamylase (OTC) deficiency is the most common inborn error of urea metabolism that can lead to hyperammonemic crises and orotic aciduria. To date, a total of 341 causative mutations within the OTC gene have been described. However, in about 20% of the patients with enzymatically confirmed OTC deficiency no mutation can be detected when sequencing of genomic DNA analyzing exons and adjacent intronic segments of the OTC gene is performed. Methods: Standard genomic DNA analysis of the OTC gene in five consecutive patients from five families revealed no mutation. Hence, liver tissue was obtained by needle sampling or open biopsy and RNA extracted from liver was analyzed. Results: Complex rearrangements of the OTC transcript (three insertions and two deletions) were found in all five patients. Conclusion: In patients with a strong suspicion of OTC deficiency despite normal results of sequencing exonic regions of the OTC gene, characterization of liver OTC mRNA is highly effective in resolving the genotype. 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| subjects | Base Sequence Child, Preschool DNA Mutational Analysis Female Genetic Testing - methods Humans Infant Infant, Newborn Liver biopsy Male mRNA analysis Neonatal Screening - methods Ornithine Carbamoyltransferase - analysis Ornithine Carbamoyltransferase - genetics Ornithine Carbamoyltransferase Deficiency Disease - diagnosis Ornithine Carbamoyltransferase Deficiency Disease - genetics Ornithine transcarbamylase RNA, Messenger - analysis Sensitivity and Specificity Urea cycle defect |
| title | Analysis of mRNA transcripts improves the success rate of molecular genetic testing in OTC deficiency |
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