. . .
Spread the love

09/29/2020

Hello readers! Today, we’ll tell you about an extremely rare yet interesting disease that goes by the name of Progeria or Hutchinson-Gilford Progeria Syndrome(HGPS). Actually, progeria is a broad category that includes multiple progeroid syndromes. Hutchinson-Gilford Progeria is the typical progeroid syndrome.

Have you ever thought, even in the wildest of your dreams, what it would feel to be a 70-year-old when it has been just 10 years since you came to this world? This is what a child suffering from this rare syndrome must be feeling. 

What is Progeria?

Progeria or Hutchinson-Gilford Progeria Syndrome(HGPS) is an extremely rare congenital genetic disease. In the patients suffering from this syndrome, the features of old age are manifested at a very early age. The prevalence rate of this disease is estimated to be around one in four to eight million newborns.

(Image by: Wikipedia)
A young girl with progeria

Symptoms, Prognosis, and Epidemiology

The symptoms of this disease include scleroderma, lipodystrophy, accelerated arteriosclerosis, ageing of the skin, alopecia, bone defects, and severe cardiovascular complications. The symptoms start appearing from 1-year of birth. At birth, the patients of this disease appear healthy. The most common reason for death (for 90% deaths) in progeroid patients is myocardial infarction and stroke resulting from atherosclerotic disease. The mean age of death in patients suffering from this disease is estimated to be around 13 years.

The genetics involved

Progeria/HGPS is generally caused by a de novo missense point mutation (single base substitution) in the LMNA gene which activates a cryptic splice site. It is inherited in an autosomal dominant fashion. However, the carriers of the disease do not live long enough to transmit it to their children. Thus, this disease is most commonly caused by de novo mutation to the LMNA gene and is not generally inherited.

(Image by: Wikipedia)
Up- A healthy cell nucleus.
Down- A progeric cell nucleus.

The cause of this disease at the molecular level

The LMNA gene encodes the nuclear lamin-A protein. Under normal cellular conditions, the LMNA gene is expressed as prelamin-A protein (precursor of lamin-A) which is farnesylated (by farnesyl transferase enzyme) and methylated as a part of post-translational modifications before being transported inside the nucleus through the nuclear pore. This farnesylated and methylated prelamin-A protein is then cleaved by a protease (Zinc Metallopeptidase) that removes the farnesylated part of the protein. After the cleavage by the endoprotease, it is now finally referred to as lamin-A.

Lamin-A protein belongs to the family of intermediate filaments. The polymer of lamin-A protein is attached to the inner nuclear membrane and provides stability to the structure and organization of the nucleus as well as chromatin.

Because of the mutation, mis-splicing occurs and a truncated version of prelamin-A protein, progerin is produced. Progerin lacks 50 amino acids at the C-terminal. Also, the progerin protein is permanently farnesylated at the C-terminal as the protease that cleaves the farnesylated C-terminal of pre-lamin-A cannot recognize the farnesylated C-terminal of progerin because the target site has been deleted due to the mutation. This implies that progerin behaves like a prelamin-A protein that is not processed properly i.e. mutant lamin-A protein. So, progerin is permanently attached to the nuclear membrane disrupting normal nuclear shape, normal cell divisions, and DNA repair. It also leads to a reduction of heterochromatin and chemical modification of histones.

(Image by: NewScientist)

Nuclear F and G actins are involved in maintaining the shape of the nucleus after cell division and gene expression respectively. The lamin-A protein has 2 binding sites for these nuclear actins. However, progerin lacks one of these two actin-binding sites.

Treatment Options

As of now, there are no F.D.A. approved treatment options available for this disease. However, current clinical trials are directed in investigating farnesyl transferase inhibitors (FTIs) (e.g. Lonafarnib) as possible treatment options. Most of the complications of this disease are attributed to the permanently farnesylated progerin protein which is permanently linked to the nuclear rim. Farnesyl transferase inhibitors prevent this farnesylation. mTOR inhibitors are also being investigated as possible treatment options.

(Image by: Wikipedia)
Left-Cells from untreated patients with progeria.
Right-Cells from patients treated with FTIs.

The current management approach is basically focussed on treating the severe cardiovascular complications through CABG and aspirin.

Clinical Trials

Clinical trials in this direction seem to be sluggish because of a lack of sufficient subjects.

Have a look at the listing of 9 clinical trials directed in investigating treatment for progeria here. (The search has been refined by using Hutchinson-Gilford Syndrome and Progeria as keywords)

Abbreviations used:

  • HGPS-Hutchinson-Gilford Progeria Syndrome
  • FDA– Food and Drug Administration
  • mTOR-mammalian Target of Rapamycin
  • FTI-Farnesyl Transferase Inhibitors
  • CABG-Coronary  Artery Bypass Grafting

References:

  1. Pubmed article: Impairment of nuclear F-actin formation and its relevance to cellular phenotypes in Hutchinson-Gilford progeria syndrome
  2. Pubmed case report: Hutchinson-Gilford Progeria Syndrome: Clinical and Molecular Characterization
  3. Pubmed: Cryptic splice sites and split genes
  4. Wikipedia: Progeria

 

Authors:

Harsh Rai-NMCTH

Himanshu Jindal-GSVM Medical College


Spread the love

12 thoughts on “Progeria: Ageing in childhood ?”

Leave a Reply

Your email address will not be published. Required fields are marked *

Social profiles