Generation and Characterization of SULT4A1 Mutant Mouse Models.

Sulfotransferase 4A1 (SULT4A1) belongs to the cytosolic sulfotransferase (SULT) superfamily of enzymes that catalyze sulfonation reactions with a variety of endogenous and exogenous substrates. Of the SULTs, SULT4A1 was shown to have the highest sequence homology between vertebrate species, yet no known function or enzymatic activity have been identified for this orphan SULT. To better understand SULT4A1 function in mammalian brain, two mutant SULT4A1 mouse strains were generated utilizing CRISPR-Cas9 technology. The first strain possessed a 28 base pair (bp) deletion (Δ28) in exon 1 that resulted in a frameshift mutation with premature termination. The second strain possessed a 12 bp in-frame deletion (Δ12) immediately preceding an active site histidine111 common to the SULT family. Homozygous pups of both strains present with severe and progressive neurological symptoms, including tremor, absence seizures, abnormal gait, ataxia, decreased weight gain compared to littermates, and death around post-natal days 21-25. SULT4A1 immunostaining was decreased in brains of heterozygous pups and not detectable in homozygous pups of both SULT4A1 mutants. SULT4A1 localization in subcellular fractions of mouse brain showed SULT4A1 associated with mitochondrial, cytosolic, and microsomal fractions, a novel localization pattern for SULTs. Finally, primary cortical neurons derived from embryonic (E15) CD-1 mice expressed high levels of SULT4A1 throughout the cell except in nuclei. Taken together, SULT4A1 appears to be an essential neuronal protein required for normal brain function, at least in mammals. Mouse models will be valuable in future studies to investigate the regulation and functions of SULT4A1 in the mammalian brain. The American Society for Pharmacology and Experimental Therapeutics.

Citation

Patrick L Garcia, Mohammed I Hossain, Shaida A Andrabi, Charles N Falany. Generation and Characterization of SULT4A1 Mutant Mouse Models. Drug metabolism and disposition: the biological fate of chemicals. 2017 Nov 06

PMID: 29109113

search → result