Hutchinson–Gilford progeroid syndrome (HGPS) is an extremely rare
autosomal dominant genetic disorder in which symptoms resembling aspects of
aging are manifested at an early age. Its occurrence is usually the result of a
sporadic germline mutation; although HGPS is genetically dominant, people rarely live long enough to have children, preventing them from passing the disorder on in a
hereditary manner. HGPS is caused by mutations that weaken the structure of the cell nucleus, making normal cell division difficult. The
histone mark
H4K20me3 is involved and caused by
de novo mutations that occur in a gene that encodes
lamin A. Lamin A is made but is not processed properly. This poor processing creates an abnormal nuclear morphology and disorganized
heterochromatin. Patients also do not have appropriate DNA repair, and they also have increased genomic instability. In normal conditions, the
LMNA gene codes for a structural protein called prelamin A, which undergoes a series of processing steps before attaining its final form, called lamin A. Prelamin A contains a "CAAX" where C is a cysteine, A an aliphatic amino acid, and X any amino acid. This motif at the
carboxyl-termini of proteins triggers three sequential enzymatic modifications. First, protein
farnesyltransferase catalyzes the addition of a farnesyl moiety to the cysteine. Second, an endoprotease that recognizes the farnesylated protein catalyzes the peptide bond's cleavage between the cysteine and -aaX. In the third step, isoprenylcysteine carboxyl methyltransferase catalyzes methylation of the carboxyl-terminal farnesyl cysteine. The
farnesylated and methylated protein is
transported through a
nuclear pore to the
interior of the nucleus. Once in the nucleus, the protein is
cleaved by a
protease called zinc metallopeptidase STE24 (
ZMPSTE24), which removes the last 15 amino acids, which includes the farnesylated cysteine. After cleavage by the protease, prelamin A is referred to as lamin A. In most mammalian cells, lamin A, along with lamin B1, lamin B2, and lamin C, makes up the
nuclear lamina, which provides shape and stability to the inner nuclear envelope. Before the late 20th century, research on progeria yielded very little information about the syndrome. In 2003, the cause of progeria was discovered to be a
point mutation in position 1824 of the
LMNA gene, which replaces a cytosine with thymine. This mutation creates a 5'
cryptic splice site within
exon 11, resulting in a shorter than normal mRNA transcript. When this shorter mRNA is
translated into protein, it produces an abnormal variant of the prelamin A protein, referred to as
progerin. Progerin's farnesyl group cannot be removed because the ZMPSTE24 cleavage site is lacking from progerin, so the abnormal protein is permanently attached to the nuclear rim. One result is that the nuclear lamina does not provide the
nuclear envelope with enough structural support, causing it to take on an abnormal shape. Since the support that the nuclear lamina normally provides is necessary for the organizing of
chromatin during
mitosis, weakening of the nuclear lamina limits the ability of the cell to divide. However, defective cell division is unlikely to be the main defect leading to progeria, particularly because children develop normally without any signs of disease until about one year of age. Farnesylated prelamin A variants also lead to defective DNA repair, which may play a role in the development of progeria. Progerin expression also leads to defects in the establishment of fibroblast cell polarity, which is also seen in physiological aging. To date, over 1,400
SNPs in the
LMNA gene are known. They can manifest as changes in mRNA, splicing, or protein amino acid sequence (e.g. Arg471Cys, Arg482Gln, Arg527Leu, Arg527Cys, and Ala529Val). Progerin may also play a role in normal human aging, since its production is activated in typical
senescent cells. A 2003 report in
Nature said that progeria may be a
de novo dominant trait. It develops during
cell division in a newly conceived zygote or in the
gametes of one of the parents. It is caused by
mutations in the
LMNA (lamin A
protein)
gene on
chromosome 1; the mutated form of lamin A is commonly known as progerin. One of the authors, Leslie Gordon, was a physician who did not know anything about progeria until her own son,
Sam, was diagnosed at 22 months. Gordon and her husband, pediatrician Scott Berns, founded the Progeria Research Foundation. A subset of progeria patients with
heterozygous mutations of
LMNA have presented an atypical form of the condition, with initial symptoms not developing until late childhood or early adolescence. These patients have had longer lifespans than those with typical-onset progeria. The general phenotype of atypical cases is consistent with typical progeria, but other factors (severity, onset, and lifespan) vary in presentation.
Lamin A Lamin A is a major component of a protein
scaffold on the inner edge of the
nucleus called the nuclear lamina that helps organize nuclear processes such as
RNA and
DNA synthesis. Prelamin A contains a CAAX box at the
C-terminus of the protein (where C is a
cysteine and A is any
aliphatic amino acids). This ensures that the cysteine is
farnesylated and allows prelamin A to bind
membranes, specifically the nuclear membrane. After prelamin A has been localized to the cell nuclear membrane, the C-terminal amino acids, including the farnesylated cysteine, are cleaved off by a specific protease. The resulting protein, now lamin A, is no longer membrane-bound and carries out functions inside the nucleus. In HGPS, the recognition site that the enzyme requires for cleavage of prelamin A to lamin A is mutated. Lamin A cannot be produced, and prelamin A builds up on the nuclear membrane, causing a characteristic nuclear
blebbing. This results in the symptoms of progeria, although the relationship between the misshapen nucleus and the symptoms is not known. A study that compared HGPS patient cells with the skin cells from young and elderly normal human subjects found similar defects in the HGPS and elderly cells, including
down-regulation of certain nuclear proteins, increased DNA damage, and
demethylation of
histone, leading to reduced
heterochromatin.
Nematodes over their lifespan show progressive lamin changes comparable to HGPS in all cells but
neurons and
gametes. These studies suggest that lamin A defects are associated with normal
aging.
Mitochondria The presence of progerin also leads to the accumulation of dysfunctional
mitochondria within the cell. These mitochondria are characterized by a swollen morphology, caused by a condensation of mtDNA and TFAM into the mitochondria, which is driven by a severe mitochondrial dysfunction (low mitochondrial membrane potential, low
ATP production, low respiration capacity and high
ROS production). Therefore, contributing substantially to the senescence phenotype. Although the explanation for this defective-mitochondria accumulation in progeria is yet to be elucidated, it has been proposed that low PGC1-α expression (important for
mitochondrial biogenesis, maintenance and function) along with low
LAMP2 protein level and
lysosome number (both important for
mitophagy: the degradation of defective mitochondria pathway), could be implicated. ==Diagnosis==