Molecular Pathology of Laminopathies

Abstract

The nuclear envelope is composed of the nuclear membranes, nuclear lamina, and nuclear pore complexes. Laminopathies are diseases caused by mutations in genes encoding protein components of the lamina and these other nuclear envelope substructures. Mutations in the single gene encoding lamin A and C, which are expressed in most differentiated somatic cells, cause diseases affecting striated muscle, adipose tissue, peripheral nerve, and multiple systems with features of accelerated aging. Mutations in genes encoding other nuclear envelope proteins also cause an array of diseases that selectively affect different tissues or organs. In some instances, the molecular and cellular consequences of laminopathy-causing mutations are known. However, even when these are understood, mechanisms explaining specific tissue or organ pathology remain enigmatic. Current mechanistic hypotheses focus on how alterations in the nuclear envelope may affect gene expression, including via the regulation of signaling pathways, or cellular mechanics, including responses to mechanical stress.

Keywords: cardiomyopathy; emerin; lamin; nuclear envelope; progeria.

Figure 1

Schematic diagram of the nuclear envelope showing the nuclear membranes, nuclear lamina, and a nuclear pore complex. Ribosomes are on the rough endoplasmic reticulum and continuous outer nuclear membrane. The nuclear pore complexes are associated with the pore membranes, and lamina and chromatin are associated with the inner nuclear membrane.

Figure 2

Schematic diagram showing select transmembrane proteins of the inner, pore, and outer membranes of the nuclear envelope. Representative transmembrane proteins that concentrate in the inner nuclear membrane are SUN1/2, emerin, LAP1, NET25, LAP2 β, MAN1, and LBR. Gp210 is a representative integral protein of the pore membrane. Nesprins concentrate in the outer nuclear membrane by binding within the perinuclear space to the luminal domains of SUN proteins and also bind to cytoskeletal filaments.

Figure 3

Progerin is a farnesylated prelamin A variant that accumulates in Hutchinson-Gilford progeria syndrome (HGPS). The cysteine-isoleucine-serine-methionine (CISM) [cysteine-aliphatic-aliphatic-any amino acid (CAAX) motif] in prelamin A triggers three sequential reactions: (①) Protein farnesyltransferase catalyzes the addition of a farnesyl moiety to the cysteine (C), (②) CAAX endopeptidase 1 or ZMPSTE24 catalyzes the endoproteolytic cleavage of the -ISM, and (③) isoprenylcysteine carboxyl methyltransferase catalyzes methylation of the farnesylcysteine. Normally, ZMPSTE24 (wild type) then recognizes farnesylated prelamin A and catalyzes an endoproteolytic cleavage (scissors), leading to removal of the last 15 amino acids, including the farnesylcysteine α-methyl ester, to generate prelamin A. In HGPS, an LMNA mutation activates an RNA cryptic splice, leading to expression of an internally truncated prelamin A variant, called progerin, that lacks 50 amino acids (red dashed line). This deletion includes the second ZMPSTE24 recognition site, and hence it is cleaved and retains a farnesylated, carboxymethylated cysteine at its carboxyl terminus.

Figure 4

Amino acid substitutions that cause Dunnigan-type familial partial lipodystrophy diminish the positivity of a surface of the lamin A/C immunoglobulin-like fold domain, while those in the same region causing striated muscle disease disrupt overall structure. (a) Localization of the amino acid substitutions (red) within the immunoglobulin-like fold domain causing striated muscle disease. (b) Three amino acid substitutions (green) causing Dunnigan-type familial partial lipodystrophy at R482, G465, and K486 that do not affect overall fold domain structure but diminish the positive charge of a solvent-exposed surface. In the disease-causing variants, glycine (neutral) at residue 465 is replaced by an aspartic acid (negative); arginine (positive) at residue 482 is replaced by a glutamine, tryptophan, or leucine (all neutral); or lysine (positive) at residue 486 is replaced by an asparagine (neutral). Figure adapted with permission from Reference .