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Life at the edge: the nuclear envelope and human disease

Key Points

  • The nuclear envelope forms a selective barrier between the nucleus and cytoplasm. It features inner and outer nuclear membranes (INM and ONM, respectively), which are spanned by nuclear pore complexes. A protein meshwork the nuclear lamina lines the nuclear face of the INM.

  • The INM contains unique membrane proteins, most of which interact with underlying chromatin and/or components of the nuclear lamina. INM proteins include emerin, as well as lamina associated protein (LAP)1 and LAP2 family members.

  • The main components of the nuclear lamina are intermediate filament proteins known as A- and B-type lamins. Lamins interact with both INM proteins and chromatin. Whereas B-type lamins are expressed in all cell types, A-type lamins are absent from early embryonic cells.

  • Defects in genes that encode nuclear lamina and lamina-associated proteins give rise to a group of human hereditary diseases known as laminopathies. Emerin and lamin A mutations are associated with X-linked and autosomal forms of Emery–Dreifuss muscular dystrophy, respectively. Other lamin A mutations give rise to disorders that include Dunnigan type familial partial lipodystrophy and type 2 Charcot-Marie-Tooth disease.

  • The disease mechanisms that are associated with lamin A mutations are not yet clear. It is possible that certain disorders, in particular cardiac and skeletal myopathies might result from nuclear structural defects that might be manifested in increased nuclear fragility. However, no single mechanism can account for all of the laminopathies

.

Abstract

A group of human diseases, known as 'laminopathies', are associated with defects in proteins of the nuclear envelope. Most laminopathy mutations have been mapped to the A-type lamin gene, which is expressed in most adult cell types. So, why should different mutations in a near-ubiquitously expressed gene be associated with various discrete tissue-restricted diseases? Attempts to resolve this paradox are uncovering new molecular interactions — both inside the nucleus and at its periphery — which indicate that the nuclear envelope has functions that go beyond mere housekeeping.

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Figure 1: Organization of the nuclear envelope.
Figure 2: Life without lamins: the pathology of Lmna-null mice.
Figure 3: Life without lamins: nuclear defects in Lmna−/− cells.
Figure 4: Laminopathy-linked LMNA mutations.
Figure 5: Three-dimensional structure of the carboxy-terminal globular domain of lamin A.

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Acknowledgements

We acknowledge J. M. Vallat and D. Salina for kindly providing figures 2C and 3B, respectively. We are also grateful to S. Shoelson and S. Dhe-Paganon for figure 5. Finally, we express our thanks to T. Sulivan, S. Kozlov, L. Mounkes and D. Escalante for their help in the preparation of this work. B.B. was supported by grants from the Canadian Institutes for Health Research and from the Alberta Heritage Foundation for Medical Research.

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DATABASES

FlyBase

Lis1

gurken

Dm0

Klar

Interpro

LEM domain

LocusLink

pRb

Syne1

OMIM

Autosomal-dominant form of EDMD

FPLD

LGMD1B

X-linked EDMD

Swiss-Prot

BAF

emerin

GFP

Lamin B3

LMNB1

LMNB2

LAP2β

LAP2γ

LIS1

LMNA

mAKAP

MAN1

nudF

Zmpste24

WormBase

UNC-83

UNC-84

Glossary

LIPODYSTROPHY

A disorder that features loss of adipocytes.

METAZOA

The animal kingdom. Includes sponges, diploblasts, protostomes and deuterostomes.

LAMINA-ASSOCIATED POLYPEPTIDE

(LAP). This is a group of integral proteins of the inner nuclear membrane (INM) that are tightly associated with the nuclear lamina. It includes the LAP1 and LAP2 families of INM proteins.

LEM DOMAIN

An 43-residue sequence that is found in the nucleoplasmic tails of several inner nuclear membrane proteins. The LEM domain is a binding site for BAF ('barrier to autoregulation factor'), a small chromatin-associated protein.

LAMIN B RECEPTOR

(LBR). A polytopic integral protein of the inner nuclear membrane that interacts with B-type lamins. LBR also interacts with chromatin and has sterol reductase activity.

FLUORESCENCE RECOVERY AFTER PHOTOBLEACHING

(FRAP). A microscopic method that can provide information on the diffusion rate of proteins in vivo.

PERINUCLEAR SPACE

(PNS). The space that is enclosed by the inner and outer nulear membrane. It is continuous with the endoplasmic reticulum lumen.

VISCERAL ENDODERM

Embryonic tissue that will give rise to the gut.

TROPHECTODERM

Embryonic tissue that contributes to the formation of the placenta.

VILLUS CRYPTS

Pits at the base of intestinal villi that contain intestinal epithelial stem cells.

X-LINKED DISEASE

An inherited disease in which the defective gene is located on the X chromosome. Recessive X-linked disorders mainly affect males.

MUSCULAR DYSTROPHY

A disorder that is characterized by muscle wasting. Histologically, dystrophic muscle features muscle-fibre death, and is accompanied by proliferation of satellite cells.

TYPE 2 INTEGRAL MEMBRANE PROTEIN

A membrane protein that contains a single transmembrane domain in which the amino terminus is cytoplasmic and the carboxyl terminus is lumenal. All INM proteins that feature a single transmembrane domain are type-2 proteins.

HAPLOINSUFFICIENT

Containing only a single functional copy of an autosomal gene.

IMMUNOGLOBULIN FOLD

A protein-domain conformation that was first described in immunoglobulins.

LISSENCEPHALY

A genetic disorder (which literally means 'smooth brain') in which there is a severe defect in neural development.

A-KINASE ANCHORING PROTEIN

(AKAP). A family of membrane-associated proteins that act as binding sites for the regulatory subunit of cAMP-dependent protein kinase (protein kinase A).

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Burke, B., Stewart, C. Life at the edge: the nuclear envelope and human disease. Nat Rev Mol Cell Biol 3, 575–585 (2002). https://doi.org/10.1038/nrm879

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