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  • Writer's pictureAbigail LaBella

From Jane to Baine

Updated: Mar 28, 2023

In 1822 Jane Wright Earl was born in England. She subsequently moved to Utah where she had 13 children and was eventually the grandmother to 85 children.


In 2017 a boy named Baine Brady Bobka tragically died of complications from Ornithine Transcarbamylase deficiency (or OTC) at the age of 7.


The Bobka family, with the help of family members and geneticists, were able to trace Baine's OTC mutation (c.-106C>A) to Jane Wright Earl.


While I have not personally been affected by OTC deficiency, I did embark on my own search for OTC mutations during my time as a research associate


What is Ornithine transcarbamylase deficiency ?

 

When we eat proteins our body breaks down (catabolizes) amino acids which results in ammonia. Ammonia (yes the cleaning supply!) is toxic to us and needs to be converted to a non-toxic substance. In humans, we convert ammonia to urea, which is excreted as urine.


The urea cycle is composed of enzymes that are able to complete the conversion of ammonia to urea. Ornithine transcarbamylase (OTC) is one of the enzymes in this pathway. Deficiencies in OTC causes ammonia to accumulate in the body and can cause severe symptoms and death.



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The OTC gene is located on the X chromosome. Individuals who are XY (males) are at a higher risk for the disease. This is because if their OTC gene contains a disease mutation, they do not have second normal copy of the gene to compensate.


OTC deficiency has an estimated frequency of one in every 50,000 to 80,000 individuals.


Some OTC deficiency mutations are de novo. This means that they occurred in the egg or sperm and are not found in the parents. Other OTC deficiency mutations are inherited. This means that the mutation was found in one or both of the parents. In the case of OTC deficiency a mother (with both an X-normal and X-disease chromosome) can have no symptoms. This mother's offspring, however, could present with the disease (with X-disease and Y chromosomes).


Diagnosis of OTC deficiency often includes a genetic test which can identify changes in the OTC gene that may cause the disease.



What kinds of mutations occur in OTC deficiency?

 

In 2010 I graduated with a Bachelors of Science and headed out into the scientific world. I was hired as a research assistant at the Children's National Medical Center in Washington, DC. My job was to determine if mutations that cause OTC deficiency could occur in regulatory regions of the gene.


Genes are sequences of DNA in our genome that encode instructions for making proteins. Proteins are the parts of our cells that provide structure and function -- they do almost everything! Gene sequences contain multiple types of information. Some of that information is the recipe for a protein. Other parts tell the cell how much of that protein to make--these are the regulatory parts of the gene.



https://microbenotes.com/exon-definition-structure-splicing-process-of-splicing/


Our group (Yoon J. Jang, Abigail L. LaBella, Timothy P. Feeney, Nancy Braverman, Mendel Tuchman, Hiroki Morizono, Nicholas Ah Mew, and Ljubica Caldovic) were able to show that nine subjects with OTC deficiency had unique mutations in the regulatory regions of the OTC gene that were likely causal for their disease.


We reported our findings in 2017 in the journal Human Mutation https://doi.org/10.1002/humu.23394


Part of my job was to use comparative genomics to identify potential regulatory regions associated with the OTC gene. Regulatory regions (which have an important function) may be more highly conserved (less change has occurred) between species. We can then use that assumption to find putative regulatory regions.


Figure 1: Promoter region of the human OTC gene. A: Sequence of the human OTC promoter. Sequence variants identified in this study are shown in red and underlined typeface. Angled arrows indicate transcription start sites in human OTC gene. Sequence variants found in study subjects are: NM_000531.5(OTC_v001):c.-106C>A, NM_000531.5(OTC_v001):c.-116C>T, NM_000531.5(OTC_v001):c.-115C>T, NM_000531.5(OTC_v001):c.-139A>G, NM_000531.5(OTC_v001):c.-142G>A, NM_000531.5(OTC_v001):c.-157T>G, NM_000531.5(OTC_v001):c.-9384G>T. B: LOGO representation of the multiple sequence alignment of OTC promoters from 36 mammals. The height of each letter corresponds to its conservation. Sequences that correspond to experimentally identified transcription factor binding sites in the rat Otc promoter are highlighted in yellow. Known transcription factor binding sites in the rat Otc promoter are shown in cyan and predicted transcription factor binding sites are shown in green


OTC deficiency into the future

 

After working at the Children's National Medical Center for a year I moved on to graduate school. While I still work in human genomics, I've only come across OTC deficiency while watching re-runs of house. A few days ago Dr. Caldovic reached out to share Baine Brady Bobka's journey with me.


OTC Deficiency can be treated, but first it must be identified. The Bobkas have made it their mission to help potential carriers identify the disease. So far they have identified 1,300+ possible carriers. They also hope that building a community of individuals who are carriers or affected by OTC Deficiency will promote possible treatments.


You can learn more here: https://www.janewrightearlotc.com/




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