Overview 

The instructions for growing and maintaining the human body are encoded within each cell. Your DNA is the instruction manual; genes are the specific sections of instructions for building different structures, and nucleotides spell out the text. Now imagine what happens when there is a spelling mistake in this manual. 

In some cases, small letter changes – essentially genetic ‘spelling mistakes’ – don't significantly alter the overall meaning of the text: the message can still be interpreted correctly, and the final product is made according to plan. But, in other cases, these spelling errors drastically alter the end product, with serious effects on essential biological processes.

This is what happens in the congenital (present from birth) genetic condition called PURA syndrome. Mutations in the PURA gene prevent the resulting protein from interacting properly with other molecules (DNA and RNA). This disruption interferes with the development of the brain and nervous system, commonly leading to neurological disorders.^1,2 

This article will explain the pathophysiology of PURA syndrome, showing how microscopic changes in cells cause the whole-body symptoms experienced by affected individuals.

What is PURA syndrome? 

PURA syndrome is an extremely rare genetic condition.  Since it was first medically described in 2014, only about 750 affected individuals worldwide have been identified by the PURA Syndrome Foundation.¹ 

It’s a monogenic disorder, meaning that an error in a single gene (the PURA gene) causes all the complications of the condition.  Symptoms are wide-ranging, affecting many organs and body functions. 

People with PURA syndrome often experience developmental delays, moderate to severe learning disabilities, and seizures (epilepsy).²

Other symptoms include:¹

• Breathing difficulties
• Difficulty swallowing (dysphagia)
• Problems walking due to poor balance and motor skills
• Speech and communication difficulties
• Bone and joint issues
• Low body temperature (hypothermia)
• Excessive tiredness (hypersomnia)
• Gastrointestinal problems
• Abnormalities of the heart, skeleton, and urinary and genital tracts
• Low muscle tone
• Vision problems

Role of the PURA gene

Each body cell has its own genetic library containing instructions for making all cellular structures, tissues and organs. These libraries are stored in the nucleus, organised into chromosomes, which keep genes (the ‘instruction manuals’) ordered and protected. The PURA gene is located on chromosome 5, at position 5q31.3.¹ 

Genes are written in a sequence of four chemical bases: adenine (A), cytosine (C), guanine (G) and thymine (T). These letters make up the language of DNA. In particular, the sequence in the PURA gene provides the instructions to produce the Pur-alpha protein.¹

The Pur-alpha protein

Pur-alpha is essential to all cells because of its ability to interact with two very important biological molecules: DNA and RNA.^3,4 

• DNA: stores genetic information in a stable, double-stranded format within chromosomes in the nucleus⁴ 
• RNA: a temporary, single-stranded transcript made from DNA, used to carry instructions to other parts of the cell⁴ 

Think of RNA as a lightweight copy of one page from a heavy instruction manual. DNA is the full manual, which is too large to carry around, while RNA is the practical transcript that can travel where needed.

Pur-alpha plays a key role in this process. Its unique structure recognises and binds to specific DNA and RNA sequences. Through these contact points, it initiates the conversion of DNA-encoded information into the single-stranded RNA form (transcription). Once in RNA form – specifically as a messenger RNA, or mRNA – Pur-alpha helps its transport out of the nucleus to ribosomes, where building blocks (amino acids) are assembled (translation).³ 

In summary, Pur-alpha acts as a traffic coordinator for genetic information, ensuring that instructions are delivered and interpreted accurately where and when they are needed.

Mutations at the PURA gene 

Mutations are genetic ‘spelling mistakes’ that can alter the PURA gene.  These can occur in different ways:

• Missense mutations: a single DNA letter change swaps one amino acid in the protein for another, which may affect its function
• Nonsense mutations: an error introduces an early "stop" signal, producing a shortened, non-functional protein
• Frameshift mutations: insertions or deletions shift the reading frame of the gene, scrambling the protein sequence
• Deletion mutations: sections of the gene are missing entirely, which may prevent the protein from being made at all

Almost all PURA gene mutations, regardless of type or location, result in the full clinical effects of PURA syndrome.³ 

Effect on DNA and RNA binding

The binding capacity of a protein (meaning its ability to attach to DNA, RNA or other molecules) depends heavily on the chemical properties of its amino acids. These determine how the protein folds into its final three-dimensional shape, much like origami instructions guide the folding of paper.

Mutations that change amino acids can alter protein folding. If the folding is disrupted, the binding site – where Pur-alpha attaches to DNA or RNA – may be distorted, blocked, or absent. This prevents Pur-alpha from recognising and binding the correct genetic sequences.

How do these changes lead to symptoms? 

When Pur-alpha protein can’t function properly, other genes become misregulated. A major role of Pur-alpha is ensuring that mRNA reaches ribosomes for protein production.³

This transport system is especially vital in the brain, where accurate delivery of mRNA supports the growth of neurons and the formation of synapses (the connections between brain cells). Without this process, neurons may not grow or signal effectively, and connections between brain cells may be weak or incomplete.^1-3

Pur-alpha also contributes to:

• Myelination: insulating nerve fibres to speed up signal transmission⁵
• Dendritic maturation: shaping the branches of neurons that receive signals⁶
• Neuronal proliferation: the growth and multiplication of brain cells⁷

When these processes are impaired:⁸

• Poor neuron growth contributes to intellectual disability
• Weak connections between neurons cause developmental delays and seizures

Beyond the brain, defective Pur-alpha also affects:¹

• Muscle tone and movement: due to disrupted nerve–muscle communication
• Feeding and breathing: caused by weak muscles and impaired neurological control
• Other organs: contributing to skeletal, cardiac, and gastrointestinal abnormalities

Summary 

Mutations in the PURA gene change the structure of the Pur-alpha protein, preventing it from binding DNA and RNA correctly. This interferes with key functions like transcription, mRNA transport, and protein synthesis, especially in the developing brain and nervous system. These molecular errors explain the neurological and systemic symptoms seen in PURA syndrome, showing how small genetic mistakes can cascade into complex developmental challenges.

FAQs

How is PURA syndrome diagnosed?

• Genetic testing (usually whole genome sequencing) is carried out using a blood or cheek swab sample from the child, and sometimes from both parents. This confirms mutations in the PURA gene at position 5q31.3.

Does the PURA gene mutation type affect the severity of PURA syndrome?

• Currently, there is insufficient data to link mutation type with symptom severity definitively.

What happens if the whole PURA gene is missing?

• Loss of one copy of the PURA gene leads to 5q31.3 microdeletion syndrome, which causes symptoms similar to PURA syndrome but often more severe, as neighbouring genes are also deleted.