Hutchinson-Gilford progeria syndrome (HGPS) is a rare disease associated with premature aging, affecting only 1 per 4-8 million live births (Rodriguez et al. 2009). People with HGPS appear normal at birth, but then commonly develop accelerated aging symptoms, including shortened stature, craniofacial disproportion, very thin skin, alopecia, and osteoporosis. Some physical facial features include prominent eyes, a thin nose with a beaked tip, thin lips, a small chin and protruding ears (Genetics Home Reference n.d.). Though, intellectual development and the development of motor skills are not affected. Death is common in the early teen years due to atherosclerosis (Mounkes et al. 2003). HGPS patients are also more at risk to strokes and heart attacks.
HGPS has previously been believed to be an inherited disease, but the genetic abnormalities believed to be linked with the disease were not showing up in the parental generation. Now, HGPS has been associated with a de novo dominant mutation in the LMNA gene (Barthélémy et al. 2015). The LMNA gene encodes A-type lamins, making up the nuclear lamina, which is a network of fibers under the nuclear envelope (Mounkes et al. 2003). The nuclear lamina functions in retention of proteins in the inner nuclear membrane, chromatin organization, DNA replication, and gene expression. Splicing of the LMNA gene transcripts yields lamin A and lamin C as its major products. B-type lamins interact with A type lamins and are encoded by Lmnb1 and Lmnb2 genes. Normally, a splice site on exon 10 splices together with exon 11 and exon 12, coding for lamin A (Eriksson et al. 2003). A-type lamins are developmentally regulated, unlike B-type, thus embryonic stem cells do not express the LMNA gene, but derivatives express it during development (Mounkes et al. 2003).
Mutations in the LMNA gene, which contains 12 exons, can cause many different disorders, specifically laminopathies, but almost all HGPS cases are due to an identical de novo single-base substitution on exon 11 on the LMNA gene, while a few do involve a different substitution within the same codon (Rodriguez et al. 2009). The most commonly seen mutation is a C to T in a CpG dinucleotide (1824C>T) because the methylated C can be deaminated to T and then miscopied, which results in lamin AΔ150 mRNA, improving the match to a consensus splice donor (Eriksson et al. 2003). The resulting mRNA activates a cryptic splice site on exon 11, resulting in a 50 amino acid deletion by the product protein near the carboxy terminus (Eriksson et al. 2003). The result is an alternative transcript called prelamin AΔ150, also known as progerin, in which its transcript was found to be more highly expressed in HGPS patients than in controls (Rodriguez et al. 2009). Also, lamin AΔ150, the mature form, is identical to lamin A except it lacks exon 10.
Prelamin AΔ150, the precursor to lamin AΔ150, is then improperly processed due to a lack of a proteolytic cleavage site for the processing enzyme Zmpste24, which removes 15 amino acids from the C terminus, including a farnesylated and carboxymethylated cysteine (more details to come on further pages). This results in a stable farnesylated and carboxymethylated lamin A protein isoform, progerin, and then cannot be processed to mature lamin A (Rodriguez et al. 2009). Then expression of progerin leads to several issues, such as irregular shaped nuclei, DNA repair defects, loss of heterochromatin, changes in histone methylation, downregulation of nuclear proteins and interferes with the onset and progression of cytokinesis All of these issues are seemingly related to the role of the nuclear lamina. Though, the role of the A-type lamin proteins in the aging processes is not completely clear, results show evidence that progerin accumulation is the major pathogenic mechanism for HGPS and other similar syndromes due to mutations near the splice site of exon 11 (Barthélémy et al. 2015).
In terms of expression levels, lamin AΔ150 transcripts were shown to be increased during in vitro cell aging in both HGPS patients and in unaffected controls, while lamin A and lamin C remained similar and unaffected (Rodriguez et al. 2009). In fact, lamin AΔ150 transcript levels in HGPS cells are present at the same levels as lamin A transcripts in the controls. In addition, studies show that the severity of the progeria is related to the ratio of progein to lamin A present. For example, patients with neonatal progeria, mutation 1821G>A, showed a high ratio of progerin to lamin A and HGPS patients (mutation 1824C>T) (Reunert et al. 2012). Different mutations can result in various ratios of progerin to lamin A and also in various splicing patterns and therefore various forms of prelamin A.