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  • Review Article
  • Published:

Human laminopathies: nuclei gone genetically awry

Nature Reviews Genetics volume 7, pages 940–952 (2006)Cite this article

Key Points

  • Over 180 mutations have been reported in the genes of the nuclear lamina, in particular LMNA, causing diseases termed 'laminopathies.' The number of identified laminopathies has steadily increased in recent years, currently including 13 known conditions.

  • LMNA encodes lamin A and lamin C, which are important components of the nuclear lamina, a dynamic protein meshwork that lies inside the inner nuclear membrane.

  • The nuclear lamina has a vital role, not only in maintenance of nuclear shape and structure, but also in transcriptional regulation, nuclear pore positioning and function, and heterochromatin organization.

  • The laminopathies show many overlapping phenotypes, which could represent a spectrum of disease rather than a set of completely distinct clinical entities. These phenotypes include skeletal and cardiac myopathies, lipodystrophies, neuropathies, skeletal dysplasias and characteristics of premature ageing.

  • As research unveils increasingly complex roles of the lamina in a diverse array of nuclear processes, evidence indicates that laminopathy phenotypes might result from a complex combination of cellular defects. These include fragile, mechanically unstable nuclei, loss of peripheral heterochromatin and other epigenetic changes, altered transcription, disrupted DNA replication, deficient DNA repair and impaired differentiation.

  • Hope for successful therapeutic strategies for the laminopathies has been mainly provided by promising work in Hutchinson–Gilford progeria syndrome, for which studies have focused on the use of farnesyltransferase inhibitors, RNAi and modified oligonucleotides.

  • Continued use of the array of mouse models of laminopathies that are currently available, the generation of new models, and further advances in cellular imaging promise to further correlate the numerous genotype–phenotype relationships among the laminopathies.

  • Future research also promises a deeper exploration into the potential links between the phenotypes of these rare diseases and the much more common conditions of atherosclerosis and ageing.

Abstract

Few genes have generated as much recent interest as LMNA, LMNB1 and LMNB2, which encode the components of the nuclear lamina. Over 180 mutations in these genes are associated with at least 13 known diseases — the laminopathies. In particular, the study of LMNA, its products and the phenotypes that result from its mutation have provided important insights into subjects ranging from transcriptional regulation, the cell biology of the nuclear lamina and mechanisms of ageing. Recent studies have begun the difficult task of correlating the genotypes of laminopathies with their phenotypes, and potential therapeutic strategies using existing drugs, modified oligonucleotides and RNAi are showing real promise for the treatment of these diseases.

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Figure 1: Structure and function of the nuclear lamina.
Figure 2: The LMNA gene and lamin A.
Figure 3: Lamin A and progerin: post-translational processing.
Figure 4: Potential mechanisms of disease.

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Authors and Affiliations

  1. Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, 50 South Drive MSC8004, Bethesda, 20892-8004, Maryland, USA

    Brian C. Capell & Francis S. Collins

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  1. Brian C. Capell
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Correspondence to Francis S. Collins.

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DATABASES

OMIM

ADLD

APL

CMT

DCM1A

EDMD

FPLD

Greenberg dysplasia

HGPS

LGMD1B

MAD

Pelger–Huet anomaly

RD

Werner syndrome (atypical)

FURTHER INFORMATION

Compilation of Known and Hypothetical Prenylated CAAX Proteins in the Human Genome

Leiden Muscular Dystrophy pages

Progeria Research Foundation

Universal Mutation Database

Glossary

Intermediate filament proteins

A large family of cytoskeletal proteins that polymerize into stable filaments of 10 nm in diameter.

Nuclear pore

Openings in the nuclear envelope through which molecules, such as nuclear proteins that are synthesized in the cytoplasm and mRNA, must pass.

Blebs

Protrusions from the surface of a cell or nucleus, usually approximately hemispherical.

Microstomia

Abnormal smallness of the mouth.

Compound heterozygous

The state of carrying a different mutation in each allele of a gene.

Pleiotropy

The action of a single gene on two or more distinct phenotypic characters.

Desmin

A muscle-specific intermediate filament.

Facultative heterochromatin

Heterochromatin that is located in positions that are composed of euchromatin in other cell types or other individuals of the same species, or even in the other homologue of a chromosome pair.

Constitutive heterochromatin

Heterochromatin that consists of highly condensed, repetitive DNA and is largely transcriptionally silent; unlike facultative heterochromatin, constitutive heterochromatin is never converted back into euchromatin.

Mesenchyme

The part of the embryonic mesoderm from which connective tissue, bone, cartilage and the circulatory and lymphatic systems develop.

Proteasome

A cytosolic protein complex that degrades proteins that have been marked for destruction by the ubiquitylation pathway.

Senescence

The state in which normal cells irreversibly stop dividing.

Herniation

The abnormal protrusion of nuclear contents through an opening or blebbed membrane.

Metabolic syndrome

A syndrome comprising hyperinsulinemia, glucose intolerance, dyslipidemia, hypertension and obesity.

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Capell, B., Collins, F. Human laminopathies: nuclei gone genetically awry. Nat Rev Genet 7, 940–952 (2006). https://doi.org/10.1038/nrg1906

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