Rapid identification of a novel complex I MT-ND3 m.10134C>A mutation in a Leigh syndrome patient.
Leigh syndrome (LS) is a rare progressive multi-system neurodegenerative disorder, the genetics of which is frequently difficult to resolve. Rapid determination of the genetic etiology of LS in a 5-year-old girl facilitated inclusion in Edison Pharmaceutical's phase 2B clinical trial of EPI-743...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2014-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4130626?pdf=render |
| _version_ | 1818146587776385024 |
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| author | David K Miller Minal J Menezes Cas Simons Lisa G Riley Sandra T Cooper Sean M Grimmond David R Thorburn John Christodoulou Ryan J Taft |
| author_facet | David K Miller Minal J Menezes Cas Simons Lisa G Riley Sandra T Cooper Sean M Grimmond David R Thorburn John Christodoulou Ryan J Taft |
| author_sort | David K Miller |
| collection | DOAJ |
| description | Leigh syndrome (LS) is a rare progressive multi-system neurodegenerative disorder, the genetics of which is frequently difficult to resolve. Rapid determination of the genetic etiology of LS in a 5-year-old girl facilitated inclusion in Edison Pharmaceutical's phase 2B clinical trial of EPI-743. SNP-arrays and high-coverage whole exome sequencing were performed on the proband, both parents and three unaffected siblings. Subsequent multi-tissue targeted high-depth mitochondrial sequencing was performed using custom long-range PCR amplicons. Tissue-specific mutant load was also assessed by qPCR. Complex I was interrogated by spectrophotometric enzyme assays and Western Blot. No putatively causal mutations were identified in nuclear-encoded genes. Analysis of low-coverage off-target mitochondrial reads revealed a previously unreported mitochondrial mutation in the proband in MT-ND3 (m.10134C>A, p.Q26K), a Complex I mitochondrial gene previously associated with LS. Targeted investigations demonstrated that this mutation was 1% heteroplasmic in the mother's blood and homoplasmic in the proband's blood, fibroblasts, liver and muscle. Enzyme assays revealed decreased Complex I activity. The identification of this novel LS MT-ND3 variant, the genomics of which was accomplished in less than 3.5 weeks, indicates that rapid genomic approaches may prove useful in time-sensitive cases with an unresolved genetic diagnosis. |
| first_indexed | 2024-12-11T12:21:44Z |
| format | Article |
| id | doaj.art-d2f5c53dd39a471fb0b84b40976efe0b |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-11T12:21:44Z |
| publishDate | 2014-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-d2f5c53dd39a471fb0b84b40976efe0b2022-12-22T01:07:30ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-0198e10487910.1371/journal.pone.0104879Rapid identification of a novel complex I MT-ND3 m.10134C>A mutation in a Leigh syndrome patient.David K MillerMinal J MenezesCas SimonsLisa G RileySandra T CooperSean M GrimmondDavid R ThorburnJohn ChristodoulouRyan J TaftLeigh syndrome (LS) is a rare progressive multi-system neurodegenerative disorder, the genetics of which is frequently difficult to resolve. Rapid determination of the genetic etiology of LS in a 5-year-old girl facilitated inclusion in Edison Pharmaceutical's phase 2B clinical trial of EPI-743. SNP-arrays and high-coverage whole exome sequencing were performed on the proband, both parents and three unaffected siblings. Subsequent multi-tissue targeted high-depth mitochondrial sequencing was performed using custom long-range PCR amplicons. Tissue-specific mutant load was also assessed by qPCR. Complex I was interrogated by spectrophotometric enzyme assays and Western Blot. No putatively causal mutations were identified in nuclear-encoded genes. Analysis of low-coverage off-target mitochondrial reads revealed a previously unreported mitochondrial mutation in the proband in MT-ND3 (m.10134C>A, p.Q26K), a Complex I mitochondrial gene previously associated with LS. Targeted investigations demonstrated that this mutation was 1% heteroplasmic in the mother's blood and homoplasmic in the proband's blood, fibroblasts, liver and muscle. Enzyme assays revealed decreased Complex I activity. The identification of this novel LS MT-ND3 variant, the genomics of which was accomplished in less than 3.5 weeks, indicates that rapid genomic approaches may prove useful in time-sensitive cases with an unresolved genetic diagnosis.http://europepmc.org/articles/PMC4130626?pdf=render |
| spellingShingle | David K Miller Minal J Menezes Cas Simons Lisa G Riley Sandra T Cooper Sean M Grimmond David R Thorburn John Christodoulou Ryan J Taft Rapid identification of a novel complex I MT-ND3 m.10134C>A mutation in a Leigh syndrome patient. PLoS ONE |
| title | Rapid identification of a novel complex I MT-ND3 m.10134C>A mutation in a Leigh syndrome patient. |
| title_full | Rapid identification of a novel complex I MT-ND3 m.10134C>A mutation in a Leigh syndrome patient. |
| title_fullStr | Rapid identification of a novel complex I MT-ND3 m.10134C>A mutation in a Leigh syndrome patient. |
| title_full_unstemmed | Rapid identification of a novel complex I MT-ND3 m.10134C>A mutation in a Leigh syndrome patient. |
| title_short | Rapid identification of a novel complex I MT-ND3 m.10134C>A mutation in a Leigh syndrome patient. |
| title_sort | rapid identification of a novel complex i mt nd3 m 10134c a mutation in a leigh syndrome patient |
| url | http://europepmc.org/articles/PMC4130626?pdf=render |
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