HUTCHINSON-GILFORD PROGERIA SYNDROME
overview---primary research review---genomic connection---phylogenetic analysis


Morgan Descoteauxemail contact


Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare dominant genetic disorder that has only affected slightly more than 100 individuals worldwide since its discovery in 1897 by Johnathan Hutchins and Hastings Gilford. HGPS is one of twelve known diseases known as laminopathies caused by a mutation of the LMNA gene. LMNA normally encodes for proteins, Lamin A and Lamin C, that help sustain nuclear stability and determine nuclear shape and size (OMIM, 2014). The nucleus of a HGPS cell is shown in Fig. 1.
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Fig. 1: Misformation of the nucleus as seen in a cell of an individual with HGPS. Permission for reuse granted by The Progeria Research Foundation, Inc.


Individuals born with HGPS appear as healthy newborns and begin to develop significant growth delays between 9-24 months of age. Patients develop a senile look with prominent scalp and eye veins and their facial features develop a "plucked bird" appearance (Kashyap, et al). Other phenotypic presentations of the disease include subcutaneous fat loss, alopecia, dental abnormalities, micrognathia (small jaw), failure-to-thrive, sclerodermatous skin, osteoporosis, stiff joints, and osteolytic lesions in bones (Fig. 2) (Davies, 2009). HGPS is a fatal disease, where those affected often do not make it past their early teens. Patients with HGPS do not suffer cognitive pre-aging, delay, or dysfunction as neuron cells do not produce LMNA. Individuals with HGPS suffer from artherosclerosis, or hardening of the arteries, essentially their whole lives. Death from heart disease like artherosclerosis is the leading cause of death in individuals with progeria, they may also succumb to strokes or heart failure (Wang, 2012). Sufferers of HGPS may also live with chronic high blood pressure, chest pain, enlarged heart, and osteoporosis making walking and movement extremely difficult (About Progeria, 2014).
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Fig. 2: Phenotypic representation of an individual with HGPS. Permission for reuse granted by The Progeria Research Foundation, Inc.


HGPS is caused by a de novo mutation (mutation in a sperm or egg cell of a parent) in only 1 birth per 8 million in the United States (OMIM, 2014). HGPS occurs from a single base pair substitution of GGC-->GGT at codon 608 within exon 11 of the LMNA gene (Wang, 2012). The substitution causes a silent gly-gly change in the codon that results in an incorrect splice site, deleting 50 amino acids in the C-terminus end of the lamin A protein. The resulting shortened protein is referred to as progerin. The deleted nucleotides include a four peptide long CAAX box farnesylation site usually cleaved off in normal cells. Since the cleavage site is missing, progerin does not undergo cleavage and remains farnesylated. The farnesylation of progerin is considered to have a multitude of consequences within the cell and may attribute greatly to the HGPS phenotype. Because progerin is never cleaved, it accumulates within the c-terminal site where it remains anchored (Fig. 3). The first trial medication targets the protein farnesylation process and has shown success in a possible therapeutic treatment of HGPS (Glynn, 2005).


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Fig. 3: Comparison of normal Lamin A processing (left) with HGPS Lamin A processing (right). The shortened progerin protein is easily seen on the right where it goes through the same processing steps as normal Lamin A until the methlyation step where the cleavage site is missing. Image available for public use retrieved from Google public domain.






















Questions considered in research:
· What implications have been made toward the molecular process of aging by studying progeria and similar lamin gene disorders?
· Will statin-like drugs be a successful long-term effective treatment for patients with HGPS?






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