Scientists identify variations in the AIPL1 gene that cause Leber congenital amaurosis

Researchers at London’s UCL Institute of Ophthalmology and Moorfields Eye Hospital have confirmed for the first time that specific variations in the AIPL1 gene cause a form of Leber congenital amaurosis (LCA).

Not all variations cause harm

Genes are sections of DNA that hold the instructions for cells to make protein molecules. They are like a sequence of letters that has to appear largely in the right order to make sense. Each gene makes a different protein, and sometimes genes can have different versions of their DNA sequence that make slightly different versions of the protein. Some variations cause harm (a ‘genetic fault’), while others may have little or no noticeable effect.

There are many natural variations in the DNA sequence for AIPL1 in the population, including in people who don’t have Leber congenital amaurosis. This means we may not always know whether AIPL1 variations found in people who do have Leber congenital amaurosis cause harm or not.

Eligible for clinical trials

However, people who test positive for the specific AIPL1 variations investigated in this study will now be eligible to take part in clinical trials as patients who might benefit from treatment. The results are a vital step towards gene therapy for Leber congenital amaurosis due to faults in the AIPL1 gene.

Clinical trials have shown that gene therapy can temporarily restore some vision to people with another form of Leber congenital amaurosis, that’s due to faults in the RPE65 gene. Research has also shown that gene therapy can rescue the light-detecting photoreceptor cells that are affected in Leber congenital amaurosis, preserving sight in mice with Leber congenital amaurosis-like sight loss caused by faults in AIPL1.

Three types of trouble

In this study Dr Jacqueline van der Spuy and team looked at AIPL1 variations they suspected were the cause of Leber congenital amaurosis in a group of patients from Moorfields. The AIPL1 gene holds instructions to make the AIPL1 protein, which works together with a protein called Hsp90 to build and maintain essential photoreceptor machinery.

Results turned up three types of malfunction caused by variations in AIPL1:

1. Some variations hold instructions for AIPL1 protein with large sections missing from the end or within the protein. Incomplete proteins are unlikely to be made by cells and so their job is not done.
2. Other variations cause protein ‘misfolding’, which changes AIPL1’s shape and leads to clumps of protein building-up inside the cell.
3. Finally, a number of variations produced AIPL1 that couldn’t bind together with the Hsp90 protein. AIPL1 can’t play its critical role in the process of turning light into an electrical signal the brain can use without the binding to Hsp90.

“Collectively, these findings provide unequivocal experimental evidence that the AIPL1 variations investigated led to significant and severe functional deficits in the resultant AIPL1 protein. Lab experiments like this allow us to draw conclusions about cause and effect,” said Dr van der Spuy. “Therefore, these variations are confirmed disease-causing mutations, and patients that harbour them will be eligible for AIPL1-targeted gene therapy, or other potential therapies targeting AIPL1.”

Better for patients

Dr Dolores M Conroy, Director of Research at Fight for Sight said: “These results not only tell us which Leber congenital amaurosis patients might benefit from targeted AIPL1 gene therapy, they will also lead to a much richer picture of the condition in terms of the signs and symptoms associated with different variants. This will mean better diagnosis for patients and genetic counselling for affected families.”

The next steps for the team are to expand the list of AIPL1 variations that are known to cause Leber congenital amaurosis. And they’ll use all of the information to develop a model of Leber congenital amaurosis in order to develop a treatment.