Lamins in Inherited Disease

Abstract

Lamins are a family of intermediate filament proteins that establish a complex protein network on the inner side of the nuclear membrane and play a critical role in preserving the structural integrity of the nuclear envelope. They also contribute to the spatial organisation of the genome and influence nuclear processes through a multitude of interactions with proteins and DNA (deoxyribonucleic acid). A large number of mutations have been identified primarily in the gene that encodes for A‐type lamins that cause a group of diseases with a broad range of clinical phenotypes collectively known as laminopathies. Many of these disorders show tissue‐restricted pathologies, indicating that even though lamins are present in the vast majority of metazoan cells, the mutations differentially influence the physiology of distinct tissues. Important clues have emerged over the past decade on the impact of disease‐causing mutations on the processes that maintain the structural and functional integrity of the nucleus.

Key Concepts

  • Lamins are components of the nuclear lamina, a network of proteins that controls nuclear structure and stiffness.
  • Lamins play critical roles in the spatial organisation of the nucleus, chromatin organisation, nucleocytoplasmic communication and mechanotransduction.
  • Mutations in genes encoding lamins are associated with a wide range of human diseases known as laminopathies.
  • Studies of lamins structure and function have shed light on the molecular mechanisms of disease pathogenesis.
  • Insights into the molecular pathology of lamins‐associated diseases create opportunities for the development of novel therapeutic strategies.

Keywords: laminopathies; muscular dystrophy; cardiomyopathy; lipodystrophy; neuropathy; leukodystrophy; progeroid disease

Figure 1. Schematic representation of nuclear lamin genes chromosomal location, and A‐ and B‐type lamins domain organisation and carboxyl terminal processing pathway. *: lamin C2 has a unique aminoterminal GNAEGR sequence, and lacks the globular head and part of the a‐helical rod domain; #: lamin B3 lacks the globular head and part on of the a‐helical rod domain.
Figure 2. Range of disease types caused by mutations in the LMNA gene or duplication of the LMNB1 gene.
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Further Reading

Camps J, Erdos MR and Ried T (2015) The role of lamin B1 for the maintenance of nuclear structure and function. Nucleus 6: 8–14.

Chojnowski A, Ong PF and Dreesen O (2015) Nuclear lamina remodelling and its implications for human disease. Cell and Tissue Research 360: 621–631.

Davidson PM and Lammerding J (2014) Broken nuclei – lamins, nuclear mechanics, and disease. Trends in Cell Biology 24: 247–256.

Dorado B and Andres V (2017) A‐type lamins and cardiovascular disease in premature aging syndromes. Current Opinion in Cell Biology 46: 17–25.

Gonzalo S and Eissenberg JC (2016) Tying up loose ends: telomeres, genomic instability and lamins. Current Opinion in Genetics & Development 37: 109–118.

Graham DM and Burridge K (2016) Mechanotransduction and nuclear function. Current Opinion in Cell Biology 40: 98–105.

Gruenbaum Y and Medalia O (2015) Lamins: the structure and protein complexes. Current Opinion in Cell Biology 32: 7–12.

Reddy S and Comai L (2012) Lamin A, farnesylation and aging. Experimental Cell Research 318: 1–7.

Sieprath T, Darwiche R and De Vos WH (2012) Lamins as mediators of oxidative stress. Biochemical and Biophysical Research Communications 421: 635–639.

Worman HJ (2012) Nuclear lamins and laminopathies. Journal of Pathology 226: 316–325.

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How to Cite close
Comai, Lucio(Jul 2017) Lamins in Inherited Disease. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0027262]