A multistage sequencing strategy pinpoints novel candidate alleles for Emery-Dreifuss muscular dystrophy and supports gene misregulation as its pathomechanism
Background: As genome-wide approaches prove difficult with genetically heterogeneous orphan diseases, we developed a new approach to identify candidate genes. We applied this to Emery-Dreifuss muscular dystrophy (EDMD), characterised by early onset contractures, slowly progressive muscular wasting,...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2020-01-01
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| Series: | EBioMedicine |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396419307972 |
| _version_ | 1831631631414198272 |
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| author | Peter Meinke Alastair R.W. Kerr Rafal Czapiewski Jose I. de las Heras Charles R. Dixon Elizabeth Harris Heike Kölbel Francesco Muntoni Ulrike Schara Volker Straub Benedikt Schoser Manfred Wehnert Eric C. Schirmer |
| author_facet | Peter Meinke Alastair R.W. Kerr Rafal Czapiewski Jose I. de las Heras Charles R. Dixon Elizabeth Harris Heike Kölbel Francesco Muntoni Ulrike Schara Volker Straub Benedikt Schoser Manfred Wehnert Eric C. Schirmer |
| author_sort | Peter Meinke |
| collection | DOAJ |
| description | Background: As genome-wide approaches prove difficult with genetically heterogeneous orphan diseases, we developed a new approach to identify candidate genes. We applied this to Emery-Dreifuss muscular dystrophy (EDMD), characterised by early onset contractures, slowly progressive muscular wasting, and life-threatening heart conduction disturbances with wide intra- and inter-familial clinical variability. Roughly half of EDMD patients are linked to six genes encoding nuclear envelope proteins, but the disease mechanism remains unclear because the affected proteins function in both cell mechanics and genome regulation. Methods: A primer library was generated to test for mutations in 301 genes from four categories: (I) all known EDMD-linked genes; (II) genes mutated in related muscular dystrophies; (III) candidates generated by exome sequencing in five families; (IV) functional candidates — other muscle nuclear envelope proteins functioning in mechanical/genome processes affected in EDMD. This was used to sequence 56 unlinked patients with EDMD-like phenotype. Findings: Twenty-one patients could be clearly assigned: 18 with mutations in genes of similar muscular dystrophies; 3 with previously missed mutations in EDMD-linked genes. The other categories yielded novel candidate genes, most encoding nuclear envelope proteins with functions in gene regulation. Interpretation: Our multi-pronged approach identified new disease alleles and many new candidate EDMD genes. Their known functions strongly argue the EDMD pathomechanism is from altered gene regulation and mechanotransduction due to connectivity of candidates from the nuclear envelope to the plasma membrane. This approach highlights the value of testing for related diseases using primer libraries and may be applied for other genetically heterogeneous orphan diseases. Funding: The Wellcome Trust, Muscular Dystrophy UK, Medical Research Council, European Community's Seventh Framework Programme “Integrated European –omics research project for diagnosis and therapy in rare neuromuscular and neurodegenerative diseases (NEUROMICS)”. Keywords: Emery-Dreifuss muscular dystrophy, Nuclear envelope, Nuclear envelope transmembrane protein, primer library, Orphan disease |
| first_indexed | 2024-12-19T05:04:19Z |
| format | Article |
| id | doaj.art-e946bd122b21483d83d43af02176d4fb |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-12-19T05:04:19Z |
| publishDate | 2020-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-e946bd122b21483d83d43af02176d4fb2022-12-21T20:35:00ZengElsevierEBioMedicine2352-39642020-01-0151A multistage sequencing strategy pinpoints novel candidate alleles for Emery-Dreifuss muscular dystrophy and supports gene misregulation as its pathomechanismPeter Meinke0Alastair R.W. Kerr1Rafal Czapiewski2Jose I. de las Heras3Charles R. Dixon4Elizabeth Harris5Heike Kölbel6Francesco Muntoni7Ulrike Schara8Volker Straub9Benedikt Schoser10Manfred Wehnert11Eric C. Schirmer12Wellcome Centre for Cell Biology, University of Edinburgh, Edinburgh, UK; Friedrich Baur Institute at the Department of Neurology, University Hospital, LMU Munich, GermanyWellcome Centre for Cell Biology, University of Edinburgh, Edinburgh, UKWellcome Centre for Cell Biology, University of Edinburgh, Edinburgh, UKWellcome Centre for Cell Biology, University of Edinburgh, Edinburgh, UKWellcome Centre for Cell Biology, University of Edinburgh, Edinburgh, UKJohn Walton Muscular Dystrophy Research Centre, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UKDepartment of Pediatric Neurology, Developmental Neurology and Social Pediatrics, University of Essen, GermanyDubowitz Neuromuscular Centre, University College London Great Ormond Street Institute of Child Health, London, UK; 1 NIHR Great Ormond Street Hospital Biomedical Research Centre, Great Ormond Street Institute of Child Health, University College London, & Great Ormond Street Hospital Trust, London, UKDepartment of Pediatric Neurology, Developmental Neurology and Social Pediatrics, University of Essen, GermanyJohn Walton Muscular Dystrophy Research Centre, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UKFriedrich Baur Institute at the Department of Neurology, University Hospital, LMU Munich, GermanyInstitute of Human Genetics, University of Greifswald (retired), Greifswald, GermanyWellcome Centre for Cell Biology, University of Edinburgh, Edinburgh, UK; Corresponding author: Prof. Dr. Eric C. Schirmer, The Wellcome Centre for Cell Biology; University of Edinburgh, Kings Buildings; Michael Swann Building, Room 5.22; Max Born Crescent; Edinburgh, EH9 3BF, UK.Background: As genome-wide approaches prove difficult with genetically heterogeneous orphan diseases, we developed a new approach to identify candidate genes. We applied this to Emery-Dreifuss muscular dystrophy (EDMD), characterised by early onset contractures, slowly progressive muscular wasting, and life-threatening heart conduction disturbances with wide intra- and inter-familial clinical variability. Roughly half of EDMD patients are linked to six genes encoding nuclear envelope proteins, but the disease mechanism remains unclear because the affected proteins function in both cell mechanics and genome regulation. Methods: A primer library was generated to test for mutations in 301 genes from four categories: (I) all known EDMD-linked genes; (II) genes mutated in related muscular dystrophies; (III) candidates generated by exome sequencing in five families; (IV) functional candidates — other muscle nuclear envelope proteins functioning in mechanical/genome processes affected in EDMD. This was used to sequence 56 unlinked patients with EDMD-like phenotype. Findings: Twenty-one patients could be clearly assigned: 18 with mutations in genes of similar muscular dystrophies; 3 with previously missed mutations in EDMD-linked genes. The other categories yielded novel candidate genes, most encoding nuclear envelope proteins with functions in gene regulation. Interpretation: Our multi-pronged approach identified new disease alleles and many new candidate EDMD genes. Their known functions strongly argue the EDMD pathomechanism is from altered gene regulation and mechanotransduction due to connectivity of candidates from the nuclear envelope to the plasma membrane. This approach highlights the value of testing for related diseases using primer libraries and may be applied for other genetically heterogeneous orphan diseases. Funding: The Wellcome Trust, Muscular Dystrophy UK, Medical Research Council, European Community's Seventh Framework Programme “Integrated European –omics research project for diagnosis and therapy in rare neuromuscular and neurodegenerative diseases (NEUROMICS)”. Keywords: Emery-Dreifuss muscular dystrophy, Nuclear envelope, Nuclear envelope transmembrane protein, primer library, Orphan diseasehttp://www.sciencedirect.com/science/article/pii/S2352396419307972 |
| spellingShingle | Peter Meinke Alastair R.W. Kerr Rafal Czapiewski Jose I. de las Heras Charles R. Dixon Elizabeth Harris Heike Kölbel Francesco Muntoni Ulrike Schara Volker Straub Benedikt Schoser Manfred Wehnert Eric C. Schirmer A multistage sequencing strategy pinpoints novel candidate alleles for Emery-Dreifuss muscular dystrophy and supports gene misregulation as its pathomechanism EBioMedicine |
| title | A multistage sequencing strategy pinpoints novel candidate alleles for Emery-Dreifuss muscular dystrophy and supports gene misregulation as its pathomechanism |
| title_full | A multistage sequencing strategy pinpoints novel candidate alleles for Emery-Dreifuss muscular dystrophy and supports gene misregulation as its pathomechanism |
| title_fullStr | A multistage sequencing strategy pinpoints novel candidate alleles for Emery-Dreifuss muscular dystrophy and supports gene misregulation as its pathomechanism |
| title_full_unstemmed | A multistage sequencing strategy pinpoints novel candidate alleles for Emery-Dreifuss muscular dystrophy and supports gene misregulation as its pathomechanism |
| title_short | A multistage sequencing strategy pinpoints novel candidate alleles for Emery-Dreifuss muscular dystrophy and supports gene misregulation as its pathomechanism |
| title_sort | multistage sequencing strategy pinpoints novel candidate alleles for emery dreifuss muscular dystrophy and supports gene misregulation as its pathomechanism |
| url | http://www.sciencedirect.com/science/article/pii/S2352396419307972 |
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