Genetic cause of newly discovered premature ageing syndrome discovered

Combining genome sequencing and cellular reprogramming has allowed researchers to uncover the genetic basis of a recently discovered rapid-ageing disorder.  

An international team of scientists has identified a new type of genetic disease, called progeroid neuropathy, which is characterised by premature ageing and neurological decline. Genomic approaches revealed that a mutation in the IVNS1ABP gene caused the condition. The researchers then used cellular reprogramming – converting patient skin cells into induced pluripotent stem (iPS) cells – to explore the cellular and molecular mechanisms by which this genetic change leads to disease.

'Our collaborator identified a family of patients whose teenaged members had whitening hair and other characteristics associated with premature ageing conditions known as progeria syndromes,' said senior author Professor Su-Chun Zhang from the Sanford Burnham Prebys Medical Discovery Institute, Canada. 'Cognitive functions are often well-preserved in these conditions, however, so it was clear from the patients' progressive loss of motor skills and neurological and intellectual deficits that this was an unknown disease.'

The study, published in Nature Communications, showed that patient-derived iPS cells carrying the IVNS1ABP mutation grew much more slowly than controls, and exhibited signs of DNA damage. Similar issues were observed when neural precursor cells (NPCs) derived from these iPS cells underwent differentiation to become neurons.

These results suggest that cells had entered a senescent state and permanently stopped multiplying. Compared with healthy controls, brain organoids grown from patient-derived iPS cells also had a more disorganised structure and featured an increase in premature differentiation of NPCs.

Further experiments showed that the IVNS1ABP mutation was linked to alterations in the dynamics of actin, a key structural protein essential for cell division. Using drugs to stabilise the actin structure improved division rates.

'It will be important to complement these findings with studies in an animal model we're developing', said first author Dr Fang Yuan. However, these results also suggest that pairing genomic approaches with cellular reprogramming and patient-derived stem cell models could be a powerful tool to explore other types of rare and poorly understood diseases.