Research Updates

Research on Citrin Deficiency

Achievement obtained by Grant from Citrin Foundation as far.

Prof Takeyori Saheki

Department of Hygiene and Health Promotion Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan

Citrin deficiency is a complex disease entity which needs lots of efforts of many researchers to make clear the pathophysiology and develop effective treatments. Since we thought it is difficult to get results only from clinical data and specimens from the patients, we have developed a mouse model for citrin deficiency, double gene knockout (KO) of citrin (Ctrn) and mitochondrial glycerol 3-phosphate dehydrogenase (mGPD), namely Ctrn/mGPD doiuble-KO mice [1]. The model mice showed a variety of symptoms similar to those of human citrin deficiency, such as hyperammonemia, which is deteriorated by sucrose administration, citrullinemia, hypoglycemia, growth retardation, fatty liver under fasting and so on [1].

We have been intending to develop therapeutic procedures for citrin deficiency by using the mouse model and reported many important issues; toxicity of carbohydrates [2,3] and therapeutic effects of protein, amino acids, sodium pyruvate and MCT [4], resulting in so far no onset of CTLN2 among the patients who had diagnosed as suffering from NICCD.

By awarded the grant from Citrin Foundation, our research has progressed rapidly. We showed that the therapeutic effect of dietary protein comes from the constituent amino acids, are identifying the most effective amino acid(s), and found that some amino acids are not suitable for the treatment. We presented the data very soon at the International Congress on Inborn Error of Metabolism held in Rio de Janeiro in September, 2017 (ICIEM2017).

We are now analyzing the metabolic pathways how the amino acids exert their therapeutic effects in order to test and use the amino acids for the treatment of the patients.

Our research projects for citrin deficiency (2017-2020) are presented below with a short explanation.

Project 1. 

Mechanism of hyperammonemia in the double-KO mice

We have shown that both functional defects of citrin to transport aspartate from mitochondria to cytosol and to transport cytosolic NADH reducing equivalent into mitochondria induce hyperammonemia, but some other factors may participate in the disease states.

Project 2.  

Effect of sterilization of laboratory chow

We found that the citrin/mGPD double-KO mice showed more severe hyperammonemia and growth retardation with autoclave-sterilized laboratory chow as compared with non-sterilized one.

Project 3.  

Find out the most effective compounds which prevent hyperammonemia and related symptoms in the double-KO mice. We will soon announce our results on this project.

Project 4.  

Liver perfusion experiment to test where effective amino acid(s) work.

We are examining if effective amino acid(s) really act on liver or not by using liver perfusion experiment.

Project 5.  

The mechanism why and how the hepatic argininosuccinate synthetase (ASS) decreases in CTLN2 patients. The reason why and how hepatic ASS decreases during the process of CTLN2 is still not known.

Project 6.  

Significance of a brain factor related to aversion to carbohydrates.

Aversion to carbohydrate is protective behavior against sugar toxicity in citrin deficiency. There should be some neuronal mechanism.

Project 7.  

Lactose preference and galactose metabolism in the double-KO mice.

Lactose is toxic for neonatal patients, but milk becomes one of the most favourite foods after one year old. What is the mechanism behind the phenomenon?

Project 8.  

Approach to possible NICCD conditions by using the mouse model.

It looks like that new-born pups of citrin/mGPD double-KO mice don’t suffer from NICCD. We want to make clear the reason why and try to make the pups ill.​


  1. Saheki T, et al. J Biol Chem 2007;282:25041-52.
  2. Yazaki M, et al. Intern Med 2005;44:188-95.
  3. Fukushima M, et al. Intern Med 2010;49:243-7.
  4. Saheki T, et al. Mol Genet Metab 2012;107:322-9

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Citrin Foundation, set up in 2016 to tackle citrin deficiency, aims to provide end-to-end support to all citrin deficiency patients, from funding research that drives effective treatments and eventually cure, and provide support to patients and families. We are a patient-driven, not-for profit organization.

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