The pivot in this story is a special patient. The young man presented with recurring infections to pediatrician in training and immunologist Fabian Kaiser of Erasmus MC. He appears to make too few antibodies. After a search, the cause comes to light: the patient has a mutation in both copies of the so-called PAX5 gene. One copy no longer works at all and the other less well. PAX5 plays a role in the development of B cells, the cells that make antibodies.
But there was something special about the young man. He also has neurological problems: autism, developmental delay and problems with movement. Autism had also previously been linked to a single mutation in the PAX5 gene, but whether this was a causal relationship remained unclear.
Mouse
The case brought together Kaiser and PAX5 specialized immunologists from the Research Institute of Molecular Pathology in Vienna with neuroscientist Aleksandra Badura from Erasmus MC. The team set out to answer the question: are the PAX5 mutations the cause of both the immunological and neurological problems?
The answer seems to be ‘yes’, the scientists write in the Journal of Experimental Medicine. A mouse with exactly the same PAX5 mutations as the young man, who the team made with the CRISPR-Cas technique, looked an awful lot like him. The mouse also had problems with antibody defenses, problems with learning and showed behavior that resembles autism.
“Quite special, because in neuroscience we don’t often see a mouse model that resembles a patient so much. You can immediately see which mice have the mutation by the way the mice move in the cage,” says Badura.
Deep in the brain
To explain the behaviour, Badura took a look inside the brains of the mice. There she found abnormalities in the cerebellum and saw that structures deep in the brain – called the substantia nigra and the area tegmentalis ventralis – were much smaller than normal. These abnormalities were also seen on an MRI scan of the young man’s brain.
By: National Care Guide
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