Conclusions and Proposals for Future Work

What are some future prospects for Type 1 Citrullinemia?

Map of mutations in ASS gene in correlation tog geographical location (Engel, Höhne, and Häberle 2009).
Figure 1: Map of mutations in ASS1 gene in correlation to geographical location (Engel, Höhne, and Häberle 2009).

Conducting Long-Term Observations

While it has been identified that specific types of mutations in the ASS1 gene correlate with different ethnicities and geographical locations (Fig. 1), there is still not enough information about how specific mutations will present in patients throughout their lives (Engel, Höhne, and Häberle 2009). Type 1 Citrullinemia can present in an early onset, severe form or the late onset, mild form.

One proposal is to monitor patients on a long-term basis in order to see how their CTLN1 presents throughout their lifetime. By noting which patients have what type of mutation and how they present throughout life (taking treatments into account), statistical evidence can be found between the two. This way, physicians can have a head start on what treatment methods to pursue by knowing the child’s mutation in the ASS gene during prenatal care.

Isolating a Better Human ASS Structure

There has indeed been a paper published with the structure of human argininosuccinate synthetase (Karlberg et al. 2008). However, the journal in which it was published is not exactly the best and most reliable. This is because the authors were forced to omit many parts of the structure in their crystallization for accuracy purposes. When analyzing the PDB structure, it was evident that the protein was incomplete and missing significant domains that were previously described in bacterial homologs in more reliable journals (Goto, Nakajima, and Hirotsu 2002).

As a result, there needs to be a new experiment that goes about isolating this enzyme in a different way. Crystallization is an intricate process that has been said to be more of an art than a science. It is very sensitive and requires just the right conditions for crystals to successfully form. Perhaps a team of researchers more experienced in the process could attempt to isolate the human structure of the enzyme. If a more accurate crystal structure of human ASS is obtained, its functionality can be better understood and the mutations that occur in the ASS gene can be further investigated to contribute to the fight against CTLN1.

Figure 2: Structure of mitochondrion. Source: Google Images
Figure 2: Structure of mitochondrion.
Source: Google Images

Finding an Alternative to Liver Transplants

Certain cases of CTLN1 involved liver transplants as a mode of treatment (Quinonez and Thoene 1993). However, this is clearly a very invasive approach. Since the patients are usually neonates or infants, mothers are probably also very apprehensive to have their newborns undergo major surgery at such a young age. Additionally, it has been reported that issues with hepatocyte mitochondria are the root of liver dysfunction in these patients due to the build up of urea cycle intermediates (Faghfoury et al. 2011).

It may be more productive to investigate how the hepatocyte mitochondria decay in response to these urea cycle intermediates. By gaining insight into this process, a medication can be developed to combat this process inside each cell as opposed to just removing the entire organ.

What can we conclude about Classic (Type 1) Citrullinemia?

Our understanding of Type 1 Citrullinemia has come a long way since its first reported case in the 1960’s. The enzyme deficiency responsible for the disease has been identified as ASS and almost 100 different mutations can occur in the ASS1 gene encoding for this enzyme. Overtime, studies have found geographic and ethnic correlations in these mutations. Additionally, bacterial homologous structures of the enzyme have been isolated as well as a preliminary human structure of ASS. Symptoms in patients are well known and therefore the disease is better identified than it was in the past. It is possible to treat the disease through different methods including surgery, diet restriction, medication, or dialysis. While there has been an incredible about of growth in the field in the past 50 years, there is still room for improvement to better these patients’ lives.


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2 Replies to “Conclusions and Proposals for Future Work”

  1. This project is really informative, great summary of the disease! I was wondering about the implications of liver transplants as treatments and I wanted to clarify: the donor liver encodes functional ASS1, which restores urea cycle activity? This surgical procedure might be replaced by a genetic procedure, such as the use of recombinant adenoviral gene transfer to implant functional human ASS1. Here is a correction of ASS activity using adenoviral gene transfer in mouse models

    I was also wondering in a disease-free context whether the same gene is expressed in both liver and kidney tissues, because the urea cycle occurs to different extents in both of these organs. Is this just a difference in epigenetic regulation?

    1. Hi Elliott. To answer your first question, yes, the idea is to restore urea cycle activity by inputting a new liver that has function ASS, but this has not always shown promising results (Faghfoury et al. 2011). The genetic procedure you found seems to be a great way to go around the invasive liver transplantation option. I had not come across this in my research, but from all these comments and suggestions on my project I have noticed when I am not specifically looking for something in the literature I have a harder time finding it and when I have something specific in mind, I find it much more easily. Maybe for future work I can look into this treatment in greater detail.

      As for your second question, I found this really awesome website called The Human Protein Atlas were you can find how expression of a protein varies in different tissues. When searching ASS1, I found that there is a larger RNA expression in kidney tissues than liver tissues, but an equal amount of protein expression. Additionally, it does not seem to be a difference in epigenetic regulation. Instead there are two different transcripts that come from exon 2 due to alternative splicing based on what organ the protein is being expressed in (Engel, Höhne, and Häberle 2009). I hope this answered your questions!

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