title: 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.
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.
authors.affiliation: Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.|Blueprint Genetics, Helsinki, Finland.
authors.forename: Tero-Pekka
authors.initials: TP
authors.lastname: Alastalo
authors.affiliation: Department of Pathology, University of Turku and Turku University Hospital, Turku, Finland.|MediCity Research Laboratory, University of Turku, Turku, Finland.
authors.forename: Gun
authors.initials: G
authors.lastname: West
authors.affiliation: Department of Pathology, University of Turku and Turku University Hospital, Turku, Finland.|MediCity Research Laboratory, University of Turku, Turku, Finland.
authors.forename: Song-Ping
authors.initials: SP
authors.lastname: Li
authors.affiliation: Department of Pathology, University of Turku and Turku University Hospital, Turku, Finland.|MediCity Research Laboratory, University of Turku, Turku, Finland.
authors.forename: Anni
authors.initials: A
authors.lastname: Keinänen
authors.affiliation: Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Mikko
authors.initials: M
authors.lastname: Helenius
authors.affiliation: Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Tiina
authors.initials: T
authors.lastname: Tyni
authors.affiliation: Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Risto
authors.initials: R
authors.lastname: Lapatto
authors.affiliation: Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Maila
authors.initials: M
authors.lastname: Turanlahti
authors.affiliation: Department of Pathology, Helsinki Central University Hospital, Helsinki, Finland.
authors.forename: Päivi
authors.initials: P
authors.lastname: Heikkilä
authors.affiliation: National Institute of Health and Welfare, Finland, and Department of Clinical Genetics, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Helena
authors.initials: H
authors.lastname: Kääriäinen
authors.affiliation: Department of Medicine, University of Eastern Finland, Kuopio, Finland.
authors.forename: Markku
authors.initials: M
authors.lastname: Laakso
authors.affiliation: Functional Architecture of the Cell Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Mauermann
authors.affiliation: Functional Architecture of the Cell Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Herrmann
authors.affiliation: Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Jaana
authors.initials: J
authors.lastname: Pihkala
authors.affiliation: Department of Pathology, University of Turku and Turku University Hospital, Turku, Finland.|MediCity Research Laboratory, University of Turku, Turku, Finland.
authors.forename: Pekka
authors.initials: P
authors.lastname: Taimen
mesh_terms: D019588:Aging, Premature / Q000235:genetics*; D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000235:genetics* / Q000473:pathology; D001483:Base Sequence; D002675:Child, Preschool; D005347:Fibroblasts / Q000378:metabolism; D056726:Genetic Association Studies; D006801:Humans; D034904:Lamin Type A / Q000235:genetics*; D008297:Male; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D017384:Sequence Deletion
chemical_list: C494847:LMNA protein, human; D034904:Lamin Type A
keywords: LMNA; dilated cardiomyopathy; intermediate filament; progeria