What mutation causes progeria?

Progeria is a rare, genetic disorder that causes premature aging in children. It affects less than 400 people worldwide (as of 2021) and is caused by a mutation in the LMNA gene (more on this later). In this article, we will dive into the specifics of what progeria is, how it manifests itself, and what exactly goes wrong at the molecular level to cause such an unusual condition.

What Is Progeria?

Progeria – or Hutchinson-Gilford progeria syndrome (HGPS) as it’s technically known – has been documented since the late 1800s. However, it wasn’t until 2003 that researchers identified its genetic basis: mutations in LMNA.

The Basics of Genetics

Before we get into how HGPS occurs let’s take a step back and quickly go over some genetics basics:

  • DNA = Deoxyribonucleic acid
  • Gene = A discrete unit of hereditary information located on a specific chromosome
  • Chromosome = Tight bundle(s) made up of DNA

Growing Up Too Fast

Children with HGPS typically appear completely normal at birth but start to show symptoms within their first year or two of life. These symptoms include stunted growth and an inability to put on weight despite having voracious appetites.

As they continue to age (and ‘age’ here really means grow older, as opposed to maturing), they encounter more age-related conditions: hair loss; joint stiffness; heart disease; osteoporosis; etcetera.

They also experience another oddity you might associate with elderly individuals – thinning skin – which makes them highly susceptible to bruising.

How Do We Grow Old?

To understand what happens during progeria (“premature aging”), let’s consider briefly how ordinary biological processes affect us as we age:

  • DNA replication gradually leads to damage
  • This is usually drastically limited by cellular repair mechanisms
  • Yet eventually, unless something kills us sooner, our bodies just can’t keep up with the scale of resulting issues

The Molecular Cause: LMNA Gene Mutation

Working back through the biological “chain reaction”, HGPS itself arises from a kind of weakened first link.

In normal body function:

• Nuclear scaffolding – i.e., the structural component responsible for holding an individual’s cell nuclei together – is made directly out of proteins called lamin A/C.

• These lamin A/C proteins are made from encoded sequences in various genes; and specifically one particular gene tends to go wrong which causes progeria.

The protein molecule is initially coded as prelamin-A before it gets posttranslationally modified (aka transformed) into lamin-A.

Unfortunately, children who develop progeria have many more defects in their production line than your average person:

[Insert Here] Mutation Explained

Children with HGPS inherit a mutated version of the LMNA gene that codes for what should be prelamin-A; but some key differences (numerous point mutations at this single location leading to aberrant splicing) mean that they end up creating irregular quantities/sizes/structures/forms of all three versions (pre-,pro-,and mature-lamins).

This undermines nuclear structure stability over time. Give or take.

How Progeria Researchers Are Working Toward Treatments and a Cure

While there isn’t yet any cure or effective treatment for progeria, researchers are making significant strides every year toward both goals.

For instance:

  • Clinical trials show promise using farnesyltransferase inhibitors – while not providing anything resembling a cure – do extend life expectancies by roughly 3 months!
  • Genetic testing keeps getting better meaning earlier detection rates
    (or possibly even prenatal selection in the future).
  • Identifying potential targeting candidate drugs for aberrant splicing, stem cells repopulation etcetera.

Progeria in Popular Culture

Being such an unusual condition that most people never encounter (nor are likely to if it stays at current incidence levels), it makes sense that progeria would become a talking/fascination point within popular culture.

Famous individuals discussed within articles/TV documentaries/films include:

• Dr.Carlos Garcia-Garcia
• LMNA-discovered Eric Schmieg
• Sam Berns

The Future of Research into HGPS

Progeria is far from fully understood, and there is still no cure. However, researchers continue to make significant headway every year, both in understanding how this disorder works and working toward effective treatments.

Who knows? Maybe one day we can add whole layers of meaning when we wish those impacted ‘many happy returns’ or their various equivalents.

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