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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
Author(s) -
Alastalo TeroPekka,
West Gun,
Li SongPing,
Keinänen Anni,
Helenius Mikko,
Tyni Tiina,
Lapatto Risto,
Turanlahti Maila,
Heikkilä Päivi,
Kääriäinen Helena,
Laakso Markku,
Mauermann Monika,
Herrmann Harald,
Pihkala Jaana,
Taimen Pekka
Publication year - 2015
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22793
Subject(s) - lmna , lamin , biology , cardiomyopathy , mutation , premature aging , genetics , medicine , heart failure , gene
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.