Overview

Progeria is a general term used to describe rare diseases that cause signs of premature ageing, including growth retardation, and the disease is always fatal.¹ Multiple forms of progeria exist and must be differentially diagnosed from each other, these include Hutchinson-Gilford progeria syndrome (HGPS), Werner syndrome, Bloom syndrome, Cockayne syndrome, and Wiedemann-Rauten-Strauch syndrome, to name a few.² This article primarily focuses on progeria in children or HGPS. Since different progeria are caused by different specific genes, parents need to consider having their child complete a genetic test to check whether the progeria symptoms are related to HGPS or other rare diseases. The disease is heritable but is more likely to occur spontaneously from a mutation in a specific gene which is present from birth (congenital).¹ The biology of progeria and how it causes growth retardation will be discussed below.

Genetics and mutations

Humans have 23 pairs (46 total) of chromosomes; one chromosome pair from each parent.³ These chromosomes contain thousands of genes, which hold information (DNA) that instructs the body (and all of its cells) tasks which they need to do. These tasks ‌involve the creation of a protein, which is then used to carry out essential biochemical reactions.³ From the 23 pairs of chromosomes, the first 22 pairs are called autosomal, while the 23^rd pair is labelled the sex chromosome (responsible for the assigned sex of an individual).⁴ Each individual will ‌receive two copies of a gene (one per chromosome pair) (Nature). 

Mutagens, or agents that cause mutations, include examples such as UV radiation, causing insertion, deletion, and substitution mutations in our DNA.^5,6 These mutations involve the insertion/deletion/substitution of nucleotides in our DNA, which causes errors to occur down the protein-making process.⁵ Mutations can also occur spontaneously. When a mutation occurs on the gene level, this leads to a domino effect where the body then cannot produce the proteins needed to carry out essential functions.³ This process, known as the central dogma of molecular biology, involves transcription (reading of the gene to produce the instructions [messenger RNA] to make a protein) and translation (the actual production of the protein).⁷

Using a simple example, if a mutation were to occur in a gene that synthesises a protein used for muscle connection, this would lead to muscle weakening. Some mutations are heritable (germline mutation), but not all mutations are not always indicative of disease (Nature). Nevertheless, it is important to check by talking to a genetic counsellor. 

Mutations or diseases can be inherited in different manners, and are named as such. There are other modes of inheritance, but for the sake of simplicity, only autosomal dominant and autosomal recessive will be discussed. Autosomal dominant inheritance refers to diseases that are caused by mutations on the autosomal chromosomes (any of the 22 pairs), while dominant refers to only needing one copy of a mutated gene to cause disease. Similarly, autosomal recessive inheritance refers to the same autosomal chromosomes but requires two copies of a mutated gene to cause disease. With HGPS, the disease is inherited in an autosomal dominant manner.¹

Genes and progeria

Although studies have shown that HGPS is inherited in an autosomal dominant manner, most cases of HGPS are from spontaneous (de-novo) mutations in a specific gene, unrelated to family history.⁸ This is also further evidenced because HGPS is a fatal disease, with an average life expectancy of 13.4 years, which ranges from 6 to 21 years old.^1,9 The disease comes from a mutation in the lamin A/C gene (LMNA gene), which is responsible for the production of lamin A and lamin C.⁸

Lamins and disease

Every cell in the human body contains a nucleus that houses our chromosomes.¹⁰ The nucleus is surrounded by a double-layered membrane responsible for preventing bigger proteins from entering which also controls the movement (release and entrance) of smaller proteins that are responsible for helping transcription and translation.10 Near the inner nuclear membrane is the nuclear lamina which is involved in providing the nucleus structural support. The nuclear lamina is made up of A-type and B-type lamins. 

A-type lamins, lamin A and lamin C, are produced by the LMNA gene, while B-type lamins are made by the LMNB1 and LMNB2 genes.¹¹ The LMNA gene can make two types (isoforms) of lamin through a process known as alternative splicing after transcription has occurred.¹¹ This process derives information from different exons (regions of the gene that code for a function) (Nature). Afterwards, during the translation process, LMNA can only form either prelamin A (immature) or (mature) lamin C.^8,11 This is due to the presence of a motif (a structural pattern), known as the CAAX box in prelamin A, that is not present in lamin C.¹¹ Prelamin A is the form that occurs before lamin A. The prelamin A only matures into lamin A after processing, which includes the addition of compound ‘tail’ (a 15-carbon compound), and the removal (cleavage) of three amino acids in the tail by a protein/enzyme called Zmpste24.^8,11 

The failure to cleave the amino acids in the tail can lead to a mutated/truncated form of lamin A (also called progerin), and is one cause of progeria.¹¹ However, this is classified differently from ‘classical’ HGPS, as this is not caused by a mutation in LMNA, but is instead caused by the inability of Zmpste24 to function as needed (ZMPSTE24 gene mutations).^8,11 Similarly to ZMPSTE24 gene mutations, a mutation in LMNA also causes a malformed prelamin A. In a specific type of LMNA gene mutation, the mutation leads to the deletion of 50 amino acids, and thus another form of truncated lamin A (progerin).¹ 

Function of lamins

As lamins provide structural support to the nuclear membrane, accumulation of progerin leads to structural deformation of the membrane.¹² When the membrane is deformed, the nucleus cannot perform fundamental tasks, such as cell replication and division (the cell cycle). These processes are necessary for the body to grow/develop, and without the processes will lead to signs of growth retardation in children with HGPS. Patients with HGPS have a rate of 50% deformed nuclear membranes in their cells whereas healthy individuals have a rate of less than 1%.¹ 

Classical HGPS versus non-classical progeria

HGPS can be divided into different types, ‘classical’ HGPS, or non-classical/atypical HGPS/progeria. These classifications are based on the type of mutation and where they are in a gene. 

Signs and symptoms

Non-classical HGPS ‌is not as severe as classical HGPS. The symptoms of classical HGPS are as listed below:

• Growth retardation 
• Wrinkled skin
• Balding
• Stiff joints 
• Hard skin (similar to scleroderma)
• Loss of body fat
• A large open soft spot on the head 
• Narrow face for the size of their head (macrocephaly)
• Beaked nose
• Teeth that come in late 
• Small (underdeveloped) jaw 
• Hip dislocation
• Cataracts
• Arthritis
• Plaque buildup in the arteries
• Stroke

In comparison, non-classical HGPS has shown:¹³

• Less retarded growth (130–145 cm, in comparison to an average of 115 cm in classical HGPS)
• Hair stays on for longer
• Fat remains longer
• Destruction of tissue surrounding bones is more severe
• Life expectancy is longer 

Classical HGPS

In 90% of HGPS cases (hence the name classical), a mutation in exon 11, specifically in position 1824 on the DNA, has a change in nucleotides, from cytosine to thymine.^1,8 This change leads to a problem known as cryptic splicing.⁸ This mutation is a ‘silent mutation,’ because the end product after transcription still leads to the same product being made. However, despite its ‘silence,’ the mutation still leads to the activation of cryptic splice sites.^8,14 This may be because of the change in the nucleotide level (cytosine to thymine), as the change in nucleotides can disrupt motifs (patterns) known as exonic splicing enhancers (ESEs).¹⁴ Disruption or modified ESEs can lead to proteins splicing in the wrong position. In classical HGPS, the cryptic splice leads to the deletion of 150 nucleotides, which cuts into the start of exon 12 and leads to the truncated prelamin A.⁸ 

The remaining 10% of classical HGPS cases is the substitution of nucleotides guanine to adenine at position 1822 on the DNA.¹⁵ This mutation causes a difference, creating a different amino acid (and therefore eventually protein) product. This leads to the same outcome, where prelamin A is truncated (progerin accumulation).

Non-classical progeria

Non-classical progeria or in this case, atypical HGPS encompass other mutations in the LMNA gene or mutations of the ZMPSTE24 gene.¹⁶ In these cases, the mutations are not necessarily from LMNA causing the accumulation of progerin but are from a variety of mutations elsewhere in the LMNA gene.^15,16 These mutations lead to different variations of the disease, particularly the age where the disease takes form, and also the severity of the disease.^15,16 If you wish to read a more detailed overview of this non-classical progeria, please take a look at Coppedè (2013)’s review.¹⁵

Summary

Progeria is an all-encompassing term that refers to an individual having characteristics of older age. Progeria in children is ‌caused by Hutchinson-Gilford progeria syndrome (HGPS), which has several symptoms such as growth retardation, hardened skin, wrinkly skin and loss of body fat. HGPS can be classified into classical or non-classical HGPS, depending on the type of mutation, in either the LMNA gene or ZMPSTE24 gene. The LMNA gene is responsible for the production of lamin A and lamin C proteins, which are used to provide structural support to the inner nuclear membrane. Mutation in the gene leads to truncated prelamin A, also called progerin, and leads to unstable structural support in the nucleus. The cells in the body then cannot replicate and divide properly, leading to stunted growth.