Genetics of Human Laminopathies


Lamins A/C, encoded by LMNA gene, are constituents of the nuclear lamina, a meshwork of proteins underneath the nuclear envelope. Human disorders linked to LMNA mutations are known as laminopathies and include cardiac and muscular dystrophies, lipodystrophies, progeroid syndromes and overlapping phenotypes. Associated with this wide clinical variability, there is also a large allelic heterogeneity that is still expanding. New links between LMNA mutations and human diseases with already known or unknown molecular cause have been established. In other cases, no evidence that a human disease is another laminopathy has been found. Moreover, the recent availability of high‐throughput sequencing technologies has made feasible to uncover the disease‐causing mutations in patients who were originally diagnosed with laminopathies but whose mutational analysis of candidate gene did not reveal any change in LMNA.

Key Concepts

  • Mutations in the LMNA gene, encoding A‐type lamin proteins, lead to a wide range of diseases known as laminopathies.
  • The clinical and allelic heterogeneity of laminopathies is still expanding.
  • Studies of the molecular mechanisms underlying laminopathies have led to advances in the understanding of lamin A functions and developing novel therapeutic strategies.
  • A group of progeroid phenotypes is phenocopy of progeroid laminopathies.
  • High‐throughput sequencing technologies have made it possible to uncover the disease‐causing mutations in genes that encode proteins involved in nuclear envelope architecture or in control of genomic stability.
  • Nuclear alterations are linked to human ageing.

Keywords: laminopathies; LMNA; lamin A/C; genetic heterogeneity; NGS

Figure 1. Overview of the aetiology, classification, diagnosis methods, nuclear consequences of defective lamin A/C and possible treatments of primary laminopathies. AR, autosomal recessive; AD, autosomal dominant.


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Further Reading

Dobrzynska A, Gonzalo S, Shanahan C and Askjaer P (2016) The nuclear lamina in health and disease. Nucleus 9: 1–16.

Evangelisti C, Cenni V and Lattanzi G (2016) Potential therapeutic effects of the mTOR inhibitors for preventing ageing and progeria‐related disorders. British Journal of Clinical Pharmacology 82 (5): 1229–1244.

Gonzalo S, Kreienkamp R and Askjaer P (2016) Hutchinson–Gilford Progeria Syndrome: a premature aging disease caused by LMNA gene mutations. Ageing Research Reviews pii S1568‐1637 (16): 30134–30139.

Madej‐Pilarczyk A and Kochański A (2016) Emery–Dreifuss muscular dystrophy: the most recognizable laminopathy. Folia Neuropathologica 54 (1): 1–8.

Perovanovic J, Dell'Orso S, Gnochi VF, et al. (2016) Laminopathies disrupt epigenomic developmental programs and cell fate. Science Translational Medicine 8 (335): 335ra58.

Vidak S and Foisner R (2016) Molecular insights into the premature aging disease progeria. Histochemistry and Cell Biology 145 (4): 401–417.

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Novelli, Giuseppe, and D'Apice, Maria Rosaria(Jan 2017) Genetics of Human Laminopathies. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0024693]