Researchers from Oregon Health and Science University developed a new mouse model that recapitulates aspects of long-chain 3-hydroxy acyl-CoA dehydrogenase deficiency (LCHADD), a type of long-chain fatty acid oxidation disorder (LCFAOD).
“This model will be useful to explore pathophysiology and treatments for LCHADD in the future,” the researchers wrote in a report they published in the journal Communications Biology.
Read more about the etiology of LCFAOD
LCHADD is caused by a mutation in the HADHA gene, which encodes the alpha subunit of a trifunctional protein.
The mouse model for generated using the CRISPR/Cas9 technique to include the G1528C mutation in the HADHA gene and recapitulated aspects of LCHADD in humans.
“Homozygous pups are less numerous than expected from Mendelian probability,” the researchers said, “but survivors exhibit similar viability with wild-type (WT) littermates.”
They also reported that the tissues of homozygote animals expressed the alpha subunit of trifunctional protein but that they oxidized less fat compared to WT animals. They also accumulated more 3-hydroxy acylcarnitines in the plasma compared to WT mice, just like patients with LCHADD.
The LCHADD animals had lower ketones with fasting compared to WT animals, exhausted earlier during treadmill exercises than WT animals, and developed dilated cardiomyopathy, all aspects of the human phenotype.
Moreover, they had decreased visual performance, cone function, and retinal pigment epithelium disruption, which may be similar to retinopathy observed in patients with LCHADD. Finally, their neurological function was affected, with impaired motor function during the wire hang test and reduced open-field activity.
“The G1528C knock-in mouse exhibits a phenotype similar to that observed in human patients,” the researchers concluded. “Future studies using this unique model of LCHADD will further elucidate the underlying pathophysiology of LCHADD and can be used to evaluate various therapeutic strategies.”
Symptoms of LCHADD include hypoketotic hypoglycemia, rhabdomyolysis, and cardiomyopathy. Other symptoms not seen in different fatty acid oxidation disorders include chorioretinopathy and peripheral neuropathy.
Gaston G, Babcock S, Ryals R, et al. A G1528C Hadha knock-in mouse model recapitulates aspects of human clinical phenotypes for long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. Commun Biol. Published online August 29, 2023. doi:10.1038/s42003-023-05268-1