The mouse model provides a new understanding of folling disease

In Norway, all newborns are tested for 25 rare genetic diseases through a neonatal screening program, the most common being phenylketonuria (abbreviated PKU), known as Folling Disease.

Every year in Norway, between 3-7 children are born with PKU, and this diagnosis has a big impact on the rest of their lives. People with PKU have to adhere to a very strict diet all their lives, where they have to avoid almost all foods that contain protein.

Failure to follow a child from birth can result in irreversible physical problems and brain damage, and optimal brain function requires consistent adherence. “

Professor Aurora Martinez, Department of Biomedicine, University of Bergen

Higher oxidative stress in mutant mice

The enzyme phenylalanine hydroxylase (PAH) breaks down the amino acid phenylalanine (Phe). People with PKU have mutations in PAH, resulting in misplaced, dysfunctional PAH. This leads to the accumulation of toxic levels of Phe in the blood and brain, and a diet without Phe begins immediately after diagnosis.

Aurora Martinez leads a group of researchers who have extensive experience working with genetic diseases associated with false mutations, especially PKU.

To better understand the disease, they made a model with mice with one of the most common human PAH mutations (Pah-R261Q).

Mutated mice and their wild-type siblings were compared in several tests, and in many of them the results were very similar for both groups of mice.

“The first difference we found was an increase in the weight of mutated male mice, and along with differences in metabolite profile (measured by Bevital) the results showed that these mice altered lipid metabolism,” Martinez says.

Together with studies in metabolic cages, where all mice received the same standard food, wild-type mice at rest were shown to use mostly carbohydrates, while mutated Pah-R261Q mice used more fat and protein as a metabolic source of fuel.

“These differences indicated greater oxidative stress in mutated mice, and this was not expected based on the usual understanding of PKU,” Martinez explains.

It may explain some of the comorbidities found in adult patients with PKU

The cause of oxidative stress has been a mystery for some time, but the explanation came when the group examined the liver of Pah-R261Q mice.

“Mutated PAH enzymes are known to form small and readily degradable aggregates. But unexpectedly large aggregates of mutated PAHs have been found here. The burden of degrading such large aggregates is a known cause of oxidative stress,” Martinez says.

Previously, PKU was seen only as a disease in which PAH mutations caused the enzyme to lose catalytic function (Phe degradation), but the results provide further understanding of how some mutations provide PAHs with a detrimental property through the formation of large aggregates.

“This may be a possible explanation for some of the comorbidities found in adult patients with PKU. In the past, this was attributed to high Phe levels or as a side effect of a strict Phe-free diet, but now there is an additional explanation based on large PAH aggregates and oxidative stress they they are applied to liver cells, ”explains Martinez.

In the future, researchers will see if they are found in this mouse model and in human patients with the same mutation, analyzing their blood for markers of oxidative stress and using them during testing of certain therapies.

The study was conducted at the Department of Biomedicine of the Medical Faculty (UiB), Bevital (Bergen) and the University Children’s Hospital, Zurich.


Journal reference:

Aubi, O., and others. (2021) Mouse Pah-R261Q detects oxidative stress associated with chemical aggregation of mutated phenylalanine hydroxylase similar to amyloid. Nature Communications.