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Mutation analysis of the lamin A/C gene (LMNA) among patients with different cardiomuscular phenotypes
  1. M Vytopil1,2,
  2. S Benedetti4,
  3. E Ricci5,13,
  4. G Galluzzi5,
  5. A Dello Russo6,
  6. L Merlini7,
  7. G Boriani8,
  8. M Gallina8,
  9. L Morandi9,
  10. L Politano10,
  11. M Moggio11,
  12. L Chiveri11,
  13. I Hausmanova-Petrusewicz12,
  14. R Ricotti1,
  15. S Vohanka2,
  16. J Toman3,
  17. D Toniolo1,4
  1. 1Institute of Molecular Genetics-CNR, Via Abbiategrasso 207, Pavia, Italy
  2. 2Department of Neurology, University Hospital Brno, Brno, Czech Republic
  3. 3Department of Internal Medicine, St Anne’s University Hospital, Brno, Czech Republic
  4. 4DIBIT-San Raffaele Scientific Institute, Milan, Italy
  5. 5Institute of Neurology
  6. 6Institute of Cardiology, Catholic University, Rome, Italy
  7. 7Neuromuscular Unit, Istituto Ortopedico Rizzoli, Bologna, Italy
  8. 8Institute of Cardiology, University of Bologna, Italy
  9. 9Besta Neurological Institute, Milan, Italy
  10. 10Department of Medical Genetics, University of Naples, Naples, Italy
  11. 11Department of Neurology, University of Milan, Milan, Italy
  12. 12Medical Research Centre, Polish Academy of Science, Warsaw, Poland
  13. 13Centre for Neuromuscular Diseases, UILDM-Rome Section, Rome, Italy
  1. Correspondence to:
 D Toniolo
 PhD, DIBIT, San Raffaele Scientific Institute, via Olgettina 58, I-20132 Milan, Italy; daniela.toniolohsr.it

https://doi.org/10.1136/jmg.40.12.e132

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    Laminopathies represent a heterogeneous group of genetic disorders characterised by mutations in the LMNA gene, which encodes two lamins, A and C, by alternative splicing of the primary transcript.1 Lamins belong to the intermediate filament multigene family and form the nuclear lamina, a mesh-like structure adjacent to the nucleoplasmic side of the inner nuclear membrane.2 They interact with emerin, the proteins encoded by the gene for the X-linked (X EDMD) form of EDMD, with several nuclear envelope proteins and with chromatin. Despite their widespread distribution and their role in nuclear architecture, alterations of lamin A/C are responsible for a number of very specific but quite heterogeneous disorders.

    The first laminopathy was the autosomal dominant form of Emery-Dreifuss muscular dystrophy (EDMD), a genetic disorder characterised by the clinical triad of early onset contractures, progressive muscular wasting and weakness with humeroperoneal distribution and cardiac conduction defects.3 The finding that emerin, an inner nuclear envelope protein, and LMNA were both involved in EDMD suggested that the lamins may represent specific and relevant factors in cardiac and skeletal muscle and that integrity of the nuclear membrane and associated structures is specifically required for muscle function.

    However, later on it was found that besides autosomal dominant Emery–Dreifuss muscular dystrophy (AD-EDMD), mutations in LMNA are responsible for six other disorders: limb girdle muscular dystrophy 1B, (LGMD1B),4,5 dilated cardiomyopathy with conduction system disease, (DCM-CD),6 Dunningan-type familial partial lipodystrophy,7–9 one recessive axonal form of Charcot-Marie-Tooth neuropathy,10 mandibuloacral dysplasia,11 and Hutchinson Gilford progeria.12,13

    Despite the very different phenotypic consequences of mutations in LMNA, and the quite large number of mutations identified, no genotype/phenotype correlation has been demonstrated, pointing to the role of factors other than lamins A and C in determining the different tissue specific phenotypes. …

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    Footnotes

    • The research was supported by Telethon-Italy, by EU Contract Euromen-Myocluster No QLG1-CT-1999-00870, and by grant IGA MZ CR NF/5919-3.