LMNA Mutation c.917T>G (p.L306R) Leads to Deleterious Hyper‐Assembly of Lamin A/C and Associates with Severe Right Ventricular Cardiomyopathy and Premature Aging |
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| Authors: | Tero‐Pekka Alastalo Gun West Song‐Ping Li Anni Keinänen Mikko Helenius Tiina Tyni Risto Lapatto Maila Turanlahti Päivi Heikkilä Helena Kääriäinen Markku Laakso Monika Mauermann Harald Herrmann Jaana Pihkala Pekka Taimen |
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| Affiliation: | 1. Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland;2. Blueprint Genetics, Helsinki, Finland;3. Department of Pathology, University of Turku and Turku University Hospital, Turku, Finland;4. MediCity Research Laboratory, University of Turku, Turku, Finland;5. Department of Pathology, Helsinki Central University Hospital, Helsinki, Finland;6. National Institute of Health and Welfare, Finland, and Department of Clinical Genetics, Helsinki University Central Hospital, Helsinki, Finland;7. Department of Medicine, University of Eastern Finland, Kuopio, Finland;8. Functional Architecture of the Cell Group, German Cancer Research Center (DKFZ), Heidelberg, Germany |
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| Abstract: | Mutations in the LMNA gene coding for the nuclear lamina proteins lamin A and its smaller splice form lamin C associate with a heterogeneous group of diseases collectively called laminopathies. Here, we describe a 2‐year‐old patient with a previously undescribed phenotype including right ventricular cardiomyopathy, progeroid features, and premature death. Sequencing of LMNA revealed a novel heterozygous de novo mutation p.L306R located in the α‐helical rod domain of A‐type lamins. Fibroblasts from the patient showed reduced proliferation and early premature replicative senescence, as characterized by progressive hyperlobulation of the nuclei, abnormally clustered centromeres, loss of lamin B1, and reorganization of promyelocytic leukemia nuclear bodies. Furthermore, the patient cells were more sensitive to double‐strand DNA breaks. Similar structural and phenotypic defects were observed in normal fibroblasts transfected with FLAG‐tagged p.L306R lamin A. Correspondingly, in vitro assembly studies revealed that the p.L306R generates a “hyper‐assembly” mutant of lamin A that forms extensive fiber arrays under physiological conditions where wild‐type lamin A is still largely soluble. In summary, we report a novel LMNA p.L306R mutation that leads to previously undescribed hyper‐assembly of lamin A, heavy distortion of nuclear shape and that manifests as right ventricular cardiomyopathy and premature aging. |
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| Keywords: | progeria dilated cardiomyopathy LMNA intermediate filament |
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