Lamins in Inherited Disease


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.


Bonne G, Di Barletta MR, Varnous S, et al. (1999) Mutations in the gene encoding lamin A/C cause autosomal dominant Emery–Dreifuss muscular dystrophy. Nature Genetics 21: 285–288.

Broers JL, Hutchison CJ and Ramaekers FC (2004) Laminopathies. Journal of Pathology 204: 478–488.

Candelario J, Borrego S, Reddy S and Comai L (2011) Accumulation of distinct prelamin A variants in human diploid fibroblasts differentially affects cell homeostasis. Experimental Cell Research 317: 319–329.

Capanni C, Mattioli E, Columbaro M, et al. (2005) Altered pre‐lamin A processing is a common mechanism leading to lipodystrophy. Human Molecular Genetics 14: 1489–1502.

Chen L, Lee L, Kudlow BA, et al. (2003) LMNA mutations in atypical Werner's syndrome. Lancet 362: 440–445.

Choi JC, Wu W, Muchir A, et al. (2012) Dual specificity phosphatase 4 mediates cardiomyopathy caused by lamin A/C (LMNA) gene mutation. Journal of Biological Chemistry 287: 40513–40524.

Coffinier C, Jung HJ, Li Z, et al. (2010) Direct synthesis of lamin A, bypassing prelamin a processing, causes misshapen nuclei in fibroblasts but no detectable pathology in mice. Journal of Biological Chemistry 285: 20818–20826.

Columbaro M, Mattioli E, Maraldi NM, et al. (2013) Oct‐1 recruitment to the nuclear envelope in adult‐onset autosomal dominant leukodystrophy. Biochimica et Biophysica Acta 1832: 411–420.

Damiano JA, Afawi Z, Bahlo M, et al. (2015) Mutation of the nuclear lamin gene LMNB2 in progressive myoclonus epilepsy with early ataxia. Human Molecular Genetics 24: 4483–4490.

Dechat T, Gesson K and Foisner R (2010) Lamina‐independent lamins in the nuclear interior serve important functions. Cold Spring Harbor Symposia on Quantitative Biology 75: 533–543.

Dialynas G, Flannery KM, Zirbel LN, et al. (2012) LMNA variants cause cytoplasmic distribution of nuclear pore proteins in Drosophila and human muscle. Human Molecular Genetics 21: 1544–1556.

Dialynas G, Shrestha OK, Ponce JM, et al. (2015) Myopathic lamin mutations cause reductive stress and activate the nrf2/keap‐1 pathway. PLoS Genetics 11: e1005231.

Duband‐Goulet I, Woerner S, Gasparini S, et al. (2011) Subcellular localization of SREBP1 depends on its interaction with the C‐terminal region of wild‐type and disease related A‐type lamins. Experimental Cell Research 317: 2800–2813.

Fong LG, Ng JK, Lammerding J, et al. (2006) Prelamin A and lamin A appear to be dispensable in the nuclear lamina. Journal of Clinical Investigation 116: 743–752.

Gilchrist S, Gilbert N, Perry P, et al. (2004) Altered protein dynamics of disease‐associated lamin A mutants. BMC Cell Biology 5: 46.

Giorgio E, Robyr D, Spielmann M, et al. (2015) A large genomic deletion leads to enhancer adoption by the lamin B1 gene: a second path to autosomal dominant adult‐onset demyelinating leukodystrophy (ADLD). Human Molecular Genetics 24: 3143–3154.

Gruenbaum Y and Foisner R (2015) Lamins: nuclear intermediate filament proteins with fundamental functions in nuclear mechanics and genome regulation. Annual Review of Biochemistry 84: 131–164.

Guelen L, Pagie L, Brasset E, et al. (2008) Domain organization of human chromosomes revealed by mapping of nuclear lamina interactions. Nature 453: 948–951.

Hegele RA, Cao H, Liu DM, et al. (2006) Sequencing of the reannotated LMNB2 gene reveals novel mutations in patients with acquired partial lipodystrophy. American Journal of Human Genetics 79: 383–389.

Holt I, Ostlund C, Stewart CL, et al. (2003) Effect of pathogenic mis‐sense mutations in lamin A on its interaction with emerin in vivo. Journal of Cell Science 116: 3027–3035.

Hutchison CJ (2014) B‐type lamins in health and disease. Seminars in Cell & Developmental Biology 29: 158–163.

Jahn D, Schramm S, Schnolzer M, et al. (2012) A truncated lamin A in the Lmna −/− mouse line: implications for the understanding of laminopathies. Nucleus 3: 463–474.

Korfali N, Wilkie GS, Swanson SK, et al. (2012) The nuclear envelope proteome differs notably between tissues. Nucleus 3: 552–564.

Kubben N, Voncken JW, Konings G, et al. (2011) Post‐natal myogenic and adipogenic developmental: defects and metabolic impairment upon loss of A‐type lamins. Nucleus 2: 195–207.

Lammerding J, Fong LG, Ji JY, et al. (2006) Lamins A and C but not lamin B1 regulate nuclear mechanics. Journal of Biological Chemistry 281: 25768–25780.

Liao CY, Anderson SS, Chicoine NH, et al. (2016) Rapamycin reverses metabolic deficits in lamin A/C‐deficient mice. Cell Reports 17: 2542–2552.

Lin ST and Fu YH (2009) miR‐23 regulation of lamin B1 is crucial for oligodendrocyte development and myelination. Disease Models & Mechanisms 2: 178–188.

Lin ST, Ptacek LJ and Fu YH (2011) Adult‐onset autosomal dominant leukodystrophy: linking nuclear envelope to myelin. Journal of Neuroscience 31: 1163–1166.

Muchir A, Pavlidis P, Decostre V, et al. (2007) Activation of MAPK pathways links LMNA mutations to cardiomyopathy in Emery–Dreifuss muscular dystrophy. Journal of Clinical Investigation 117: 1282–1293.

Muchir A, Reilly SA, Wu W, et al. (2012a) Treatment with selumetinib preserves cardiac function and improves survival in cardiomyopathy caused by mutation in the lamin A/C gene. Cardiovascular Research 93: 311–319.

Muchir A, Wu W, Choi JC, et al. (2012b) Abnormal p38alpha mitogen‐activated protein kinase signaling in dilated cardiomyopathy caused by lamin A/C gene mutation. Human Molecular Genetics 21: 4325–4333.

Muchir A, Kim YJ, Reilly SA, et al. (2013) Inhibition of extracellular signal‐regulated kinase 1/2 signaling has beneficial effects on skeletal muscle in a mouse model of Emery–Dreifuss muscular dystrophy caused by lamin A/C gene mutation. Skeletal Muscle 3: 17.

Navarro CL, De Sandre‐Giovannoli A, Bernard R, et al. (2004) Lamin A and ZMPSTE24 (FACE‐1) defects cause nuclear disorganization and identify restrictive dermopathy as a lethal neonatal laminopathy. Human Molecular Genetics 13: 2493–2503.

Nikolova V, Leimena C, McMahon AC, et al. (2004) Defects in nuclear structure and function promote dilated cardiomyopathy in lamin A/C‐deficient mice. Journal of Clinical Investigation 113: 357–369.

Padiath QS, Saigoh K, Schiffmann R, et al. (2006) Lamin B1 duplications cause autosomal dominant leukodystrophy. Nature Genetics 38: 1114–1123.

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

Ramos FJ, Chen SC, Garelick MG, et al. (2012) Rapamycin reverses elevated mTORC1 signaling in lamin A/C‐deficient mice, rescues cardiac and skeletal muscle function, and extends survival. Science Translational Medicine 4: 144ra103.

Reddy S and Comai L (2016) Recent advances in understanding the role of lamins in health and disease. F1000Res 5: 2536.

Robson MI, de Las Heras JI, Czapiewski R, et al. (2016) Tissue‐Specific Gene Repositioning by Muscle Nuclear Membrane Proteins Enhances Repression of Critical Developmental Genes during Myogenesis. Molecular Cell 62: 834–847.

Rusinol AE and Sinensky MS (2006) Farnesylated lamins, progeroid syndromes and farnesyl transferase inhibitors. Journal of Cell Science 119: 3265–3272.

Schreiber KH and Kennedy BK (2013) When lamins go bad: nuclear structure and disease. Cell 152: 1365–1375.

Shimi T, Kittisopikul M, Tran J, et al. (2015) Structural organization of nuclear lamins A, C, B1, and B2 revealed by superresolution microscopy. Molecular Biology of the Cell 26: 4075–4086.

Sullivan T, Escalante‐Alcalde D, Bhatt H, et al. (1999) Loss of A‐type lamin expression compromises nuclear envelope integrity leading to muscular dystrophy. Journal of Cell Biology 147: 913–920.

Swift J, Ivanovska IL, Buxboim A, et al. (2013) Nuclear lamin‐A scales with tissue stiffness and enhances matrix‐directed differentiation. Science 341: 1240104.

Turgay Y, Eibauer M, Goldman AE, et al. (2017) The molecular architecture of lamins in somatic cells. Nature 543: 261–264.

Vadrot N, Duband‐Goulet I, Cabet E, et al. (2015) The p.R482W substitution in A‐type lamins deregulates SREBP1 activity in Dunnigan‐type familial partial lipodystrophy. Human Molecular Genetics 24: 2096–2109.

Young SG, Jung HJ, Lee JM and Fong LG (2014) Nuclear lamins and neurobiology. Molecular and Cellular Biology 34: 2776–2785.

Zhang H, Kieckhaefer JE and Cao K (2013) Mouse models of laminopathies. Aging Cell 12: 2–10.

Zwerger M, Jaalouk DE, Lombardi ML, et al. (2013) Myopathic lamin mutations impair nuclear stability in cells and tissue and disrupt nucleo‐cytoskeletal coupling. Human Molecular Genetics 22: 2335–2349.

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. [doi: 10.1002/9780470015902.a0027262]