Dominant collagen XII mutations cause a distal myopathy
Abstract Objective To characterize the natural history and clinical features of myopathies caused by mono‐allelic, dominantly acting pathogenic variants in COL12A1. Methods Patients with dominant COL12A1‐related myopathies were characterized by history and clinical examination, muscle imaging, and g...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2019-10-01
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| Series: | Annals of Clinical and Translational Neurology |
| Online Access: | https://doi.org/10.1002/acn3.50882 |
| _version_ | 1818561801382526976 |
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| author | Payam Mohassel Teerin Liewluck Ying Hu Daniel Ezzo Tracy Ogata Dimah Saade Sarah Neuhaus Véronique Bolduc Yaqun Zou Sandra Donkervoort Livija Medne Charlotte J. Sumner P. James B. Dyck Klaas J. Wierenga Gihan Tennekoon Richard S. Finkel Jiani Chen Thomas L. Winder Nathan P. Staff A. Reghan Foley Manuel Koch Carsten G. Bönnemann |
| author_facet | Payam Mohassel Teerin Liewluck Ying Hu Daniel Ezzo Tracy Ogata Dimah Saade Sarah Neuhaus Véronique Bolduc Yaqun Zou Sandra Donkervoort Livija Medne Charlotte J. Sumner P. James B. Dyck Klaas J. Wierenga Gihan Tennekoon Richard S. Finkel Jiani Chen Thomas L. Winder Nathan P. Staff A. Reghan Foley Manuel Koch Carsten G. Bönnemann |
| author_sort | Payam Mohassel |
| collection | DOAJ |
| description | Abstract Objective To characterize the natural history and clinical features of myopathies caused by mono‐allelic, dominantly acting pathogenic variants in COL12A1. Methods Patients with dominant COL12A1‐related myopathies were characterized by history and clinical examination, muscle imaging, and genetic analysis. Pathogenicity of the variants was assessed by immunostaining patient‐derived dermal fibroblast cultures for collagen XII. Results Four independent families with childhood‐onset weakness due to novel, dominantly acting pathogenic variants in COL12A1 were identified. Adult patients exhibited distal‐predominant weakness. Three families carried dominantly acting glycine missense variants, and one family had a heterozygous, intragenic, in‐frame deletion of exon 52 of COL12A1. All pathogenic variants resulted in increased intracellular retention of collagen XII in patient‐derived fibroblasts as well as loss of extracellular, fibrillar collagen XII deposition. Since haploinsufficiency for COL12A1 is largely clinically asymptomatic, we designed and evaluated small interfering RNAs (siRNAs) that specifically target the mutant allele containing the exon 52 deletion. Immunostaining of the patient fibroblasts treated with the siRNA showed a near complete correction of collagen XII staining patterns. Interpretation This study characterizes a distal myopathy phenotype in adults with dominant COL12A1 pathogenic variants, further defining the phenotypic spectrum and natural history of COL12A1‐related myopathies. This work also provides proof of concept of a precision medicine treatment approach by proposing and validating allele‐specific knockdown using siRNAs specifically designed to target a patient’s dominant COL12A1 disease allele. |
| first_indexed | 2024-12-14T00:55:28Z |
| format | Article |
| id | doaj.art-8783869b7a1b4355a5a49ddec2739631 |
| institution | Directory Open Access Journal |
| issn | 2328-9503 |
| language | English |
| last_indexed | 2024-12-14T00:55:28Z |
| publishDate | 2019-10-01 |
| publisher | Wiley |
| record_format | Article |
| series | Annals of Clinical and Translational Neurology |
| spelling | doaj.art-8783869b7a1b4355a5a49ddec27396312022-12-21T23:23:36ZengWileyAnnals of Clinical and Translational Neurology2328-95032019-10-016101980198810.1002/acn3.50882Dominant collagen XII mutations cause a distal myopathyPayam Mohassel0Teerin Liewluck1Ying Hu2Daniel Ezzo3Tracy Ogata4Dimah Saade5Sarah Neuhaus6Véronique Bolduc7Yaqun Zou8Sandra Donkervoort9Livija Medne10Charlotte J. Sumner11P. James B. Dyck12Klaas J. Wierenga13Gihan Tennekoon14Richard S. Finkel15Jiani Chen16Thomas L. Winder17Nathan P. Staff18A. Reghan Foley19Manuel Koch20Carsten G. Bönnemann21National Institutes of Health, NINDS, NNDCS Bethesda MarylandDepartment of Neurology Mayo Clinic Rochester MinnesotaNational Institutes of Health, NINDS, NNDCS Bethesda MarylandNational Institutes of Health, NINDS, NNDCS Bethesda MarylandNational Institutes of Health, NINDS, NNDCS Bethesda MarylandNational Institutes of Health, NINDS, NNDCS Bethesda MarylandNational Institutes of Health, NINDS, NNDCS Bethesda MarylandNational Institutes of Health, NINDS, NNDCS Bethesda MarylandNational Institutes of Health, NINDS, NNDCS Bethesda MarylandNational Institutes of Health, NINDS, NNDCS Bethesda MarylandRoberts Individualized Medical Genetics Center, Division of Human Genetics Children’s Hospital of Philadelphia Philadelphia PennsylvaniaDepartments of Neurology and Neuroscience Johns Hopkins University School of Medicine Baltimore MarylandDepartment of Neurology Mayo Clinic Rochester MinnesotaDepartment of Clinical Genomics Mayo Clinic Jacksonville FloridaDivision of Neurology Children's Hospital of Philadelphia Philadelphia PennsylvaniaDepartment of Pediatrics Nemours Children’ Health System Orlando FloridaDivision of Genomic Diagnostics Children’s Hospital of Philadelphia Philadelphia PennsylvaniaInvitae Corporation San Francisco CaliforniaDepartment of Neurology Mayo Clinic Rochester MinnesotaNational Institutes of Health, NINDS, NNDCS Bethesda MarylandInstitute for Dental Research and Oral Musculoskeletal Biology, Center for Biochemistry, Medical Faculty University of Cologne Cologne GermanyNational Institutes of Health, NINDS, NNDCS Bethesda MarylandAbstract Objective To characterize the natural history and clinical features of myopathies caused by mono‐allelic, dominantly acting pathogenic variants in COL12A1. Methods Patients with dominant COL12A1‐related myopathies were characterized by history and clinical examination, muscle imaging, and genetic analysis. Pathogenicity of the variants was assessed by immunostaining patient‐derived dermal fibroblast cultures for collagen XII. Results Four independent families with childhood‐onset weakness due to novel, dominantly acting pathogenic variants in COL12A1 were identified. Adult patients exhibited distal‐predominant weakness. Three families carried dominantly acting glycine missense variants, and one family had a heterozygous, intragenic, in‐frame deletion of exon 52 of COL12A1. All pathogenic variants resulted in increased intracellular retention of collagen XII in patient‐derived fibroblasts as well as loss of extracellular, fibrillar collagen XII deposition. Since haploinsufficiency for COL12A1 is largely clinically asymptomatic, we designed and evaluated small interfering RNAs (siRNAs) that specifically target the mutant allele containing the exon 52 deletion. Immunostaining of the patient fibroblasts treated with the siRNA showed a near complete correction of collagen XII staining patterns. Interpretation This study characterizes a distal myopathy phenotype in adults with dominant COL12A1 pathogenic variants, further defining the phenotypic spectrum and natural history of COL12A1‐related myopathies. This work also provides proof of concept of a precision medicine treatment approach by proposing and validating allele‐specific knockdown using siRNAs specifically designed to target a patient’s dominant COL12A1 disease allele.https://doi.org/10.1002/acn3.50882 |
| spellingShingle | Payam Mohassel Teerin Liewluck Ying Hu Daniel Ezzo Tracy Ogata Dimah Saade Sarah Neuhaus Véronique Bolduc Yaqun Zou Sandra Donkervoort Livija Medne Charlotte J. Sumner P. James B. Dyck Klaas J. Wierenga Gihan Tennekoon Richard S. Finkel Jiani Chen Thomas L. Winder Nathan P. Staff A. Reghan Foley Manuel Koch Carsten G. Bönnemann Dominant collagen XII mutations cause a distal myopathy Annals of Clinical and Translational Neurology |
| title | Dominant collagen XII mutations cause a distal myopathy |
| title_full | Dominant collagen XII mutations cause a distal myopathy |
| title_fullStr | Dominant collagen XII mutations cause a distal myopathy |
| title_full_unstemmed | Dominant collagen XII mutations cause a distal myopathy |
| title_short | Dominant collagen XII mutations cause a distal myopathy |
| title_sort | dominant collagen xii mutations cause a distal myopathy |
| url | https://doi.org/10.1002/acn3.50882 |
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