Ornithine Transcarbamylase (OTC) is a mitochondrial transferase protein involved in the urea cycle. It catalyzes the reaction between ornithine and carbamoyl phosphate to produce citrulline and phosphate. This process is essential for the detoxification of ammonia to urea. Due to its important role, mutations in the OTC gene can lead to biochemically inactive or absent OTC resulting in OTC Deficiency (OTCD). Patient outcomes depend on the mutation and the severity of the symptoms. Early onset OTCD, which presents during the neonatal period, is often fatal, while late onset OTCD tends to be milder. More than 420 mutations in the gene have been identified; 270 are known point mutations. Even though mutations have been identified, little work has been done to characterize these variants biochemically. Each variant was analyzed using a computational tool developed here, Partial Order Optimum Likelihood (POOL). Then to prioritize experimental characterization, a list of mutations that showed the greatest variation in computed chemical properties from those of wildtype OTC were compiled to gain insight about these specific mutations. The goals are better understanding of the disease and the search for personalized treatments in the future.

Determining the biochemical effects of ornithine transcarbamylase disease associated variants

ACS Spring 2022

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