The Premature Aging Syndrome : Hutchinson-Gilford Progeria Syndrome—Insights Into Normal Aging

Lamin A

HGPS is a member of the family of genetic diseases known as the laminopathies, whose causal mutations lie along the LMNA gene (located at 1q21.2). The LMNA gene codes for at least four isoforms—two major (lamin A and lamin C) and two minor (lamin AΔ10 and lamin C2). These diverge in structure, function, expression pattern, and binding partners. Only the lamin A isoform is associated with mammalian disease. The lamin proteins are the principal proteins of the nuclear lamina, a structure located inside the inner nuclear membrane. Lamin A, like all lamin molecules, contains an N-terminal head domain, coiled coil α-helical rod domain, and carboxy terminal tail domain. Tail domains contain the nuclear localization sequences essential for protein targeting to the nucleus after posttranslational processing in the endoplasmic reticulum. Lamin monomers first dimerize, the dimers associate in a head to tail fashion, and then finally associate laterally. The primary RNA transcript of lamin A contains 12 exons that are spliced and then translated to produce a lamin A precursor, prelamin A. This precursor is posttranslationally processed via farnesylation, cleavage of the last three amino acid residues at its carboxy terminal, and methyl esterification ( Figure 10-2 ). Prelamin A subsequently undergoes proteolysis of its C-terminal 18 amino acids, which includes the farnesyl group, to become mature lamin A. The loss of the farnesyl anchor presumably releases prelamin from the nuclear membrane, rendering it free to participate in the multiprotein nuclear scaffold complex just internal to the nuclear membrane, affecting nuclear structure and function. The integrity of the lamina is crucial to many cellular functions, including mitosis, creating and maintaining structural integrity of the nuclear scaffold, DNA replication, RNA transcription, organization of the nucleus, nuclear pore assembly, chromatin function, cell cycling, and apoptosis.

Mutations in LMNA Cause Hutchinson-Gilford Progeria Syndrome

HGPS is almost always a sporadic autosomal dominant disease. There have been two identified cases of germline mosaicism (see the Progeria Research Foundation diagnostics program at www.progeriaresearch.org ). Classic HGPS patients have a single C to T transition at nucleotide 1824 that does not change the translated amino acid (Gly608Gly), but activates a seldom used internal splice site, resulting in the deletion of 150 base pairs in the 3′ portion of exon 11 (see Figure 10-2 ). A minority of patients with atypical HGPS have progerin-producing pathogenic single-base mutations within the spliceosome recognition sequence of intron 11 of LMNA . In these cases, instead of optimizing the internal splice site, the mutation decreases use of the intronic splice site in favor of the internal site. In classic and atypical HGPS, progerin is produced. Translation followed by posttranslational processing of this altered mRNA produces a shortened abnormal protein with a 50–amino acid deletion near its C-terminal end, termed progerin , or lamin AΔ50. The 50–amino acid deletion does not affect the ability of progerin to localize to the nucleus or dimerize because the necessary components for these functions are not deleted. Importantly, however, it does remove the recognition site that leads to proteolytic cleavage of the terminal 18 amino acids of prelamin A (see Figure 10-2 ), along with the phosphorylation site(s) involved in the dissociation and reassociation of the nuclear membrane at each cell division.

The multisystem and primarily postnatal disease manifestation in HGPS is not surprising, because lamin A is normally expressed by most differentiated cells, preserving function in undifferentiated cells that dominate fetal development (reviewed by Gruenbaum and colleagues ). Lamin A expression is developmentally regulated and displays cell and tissue specificity, primarily in differentiated cells, including fibroblasts, vascular smooth muscle cells, and vascular endothelial cells. The alternate splicing in HGPS leads to decreased levels of lamin A. One chromosome is not mutated and transcribes lamin A normally, whereas the other is mutated, and the splicing machinery transcribes progerin instead of lamin A for some fraction of the time (estimated to be from 40% to 80%). However, decreasing lamin A levels does not seem to affect cell function significantly. A mouse model entirely lacking lamin A has shown no signs of disease. HGPS is therefore a dominant negative disease; it is the action of progerin, not the diminution of lamin A, that causes the disease phenotype.