The first time I recognized that I might have a genetic mutation was in a biology class taught by Dr. Mark Christensen at Georgetown College. At the time, new discoveries had just been made in obesity research highlighting the importance of Leptin in hunger satiety. It was with interest that I noted similarities in myself and those leptin deficient mice, and for the first time I wondered if I might have a genetic mutation. I put the thought aside because, as many people told me, I was just being lazy.
I kept telling myself that I was lazy, that I hadn't tried hard enough, as I tried diet after diet; I eventually had gastric sleeve surgery. For years I couldn't understand why I wasn't losing weight after the gastric sleeve. I was doing what the doctors told me, even exercising (which I despise) and over a year later had only lost about 80 lbs. Other people I knew personally were losing about 30 lbs per month on average. Some people never changed their lifestyle at all and still lost massive amounts of weight. It was extremely frustrating, and really contributed to my negative self talk and negative self image.
I continued to search for answers, going from doctor to doctor. In 2019, I came across a Facebook add for a study at Vanderbilt Children's Hospital on childhood obesity. The study was requesting DNA samples from people who suffered from childhood obesity. I thought, "What the hell?" and sent in a sample. It was months before I received any word on the results.
In the interim, I had landed upon a local OB/GYN who specializes in hormonal imbalances. We discovered that my T3 (Thyroid hormone) was at the bottom of the range, but not low enough to flag on most lab reports. I started medication and began to feel relief from the extreme exhaustion with which I had been suffering. I also asked to be tested for Cushing's Disease, due to having many similar symptoms; the test was negative. Then to my surprise, I received the results back from the Vanderbilt Children's Childhood Obesity study - I had a rare heterozygous genetic mutation of the peptide SRC-1 (also referred to as NCOA-1). This peptide is a steroid coactivator, which is needed to help activate other proteins and receptors in the body. Current numbers reflect that > 23,000 people in the US have a mutation on this gene, and the mutations have only been studied in mice. Approximately 1 in 2000 people are estimated to have a mutation that affects the MC4R signaling pathway, which is a hunger signaling pathway. More about what happens with the loss of function of the MC4R pathway at Uncommon Obesity.
However, what various studies did show was that SRC-1 is involved in the transport of hormones throughout the body via receptor binding, transcription, regulation of body responses to drugs, various aspects of brain development, estrogen cycle, and more. There are at least 60 known dependencies in molecular function, and other biological processes.
More about the SRC-1/NCOA-1 peptide here.
After discovering the mutated gene, I was invited to participate in a clinical trial of a new drug called "Setmelanotide" which now has FDA approval under the brand name "Imcivree." I've been in the trial for more than a year, but alas haven't seen significant weight loss. However other genetic types, such as those with Leptin deficiency, have! Despite my lack of weight loss, things I personally thought the medicine helped me with were: hunger associated migraines, blood sugar drops, daily hunger levels, and nausea. It is a bittersweet month, as I have decided to withdraw from the trial to try to start a family; pregnant and nursing women are not allowed in the study. I will forever be grateful to have participated in this clinical trial, and hope that my genetic material donations eventually lead scientists toward a solution that will be more effective for people like me.
Despite the hurdles I've faced, and the continued frustration, I am glad to be armed with knowledge and resources. Thank you to all of the scientists researching these little known diseases and thank you to my educators!
A special thanks goes to Dr. Mark Christensen; without your lesson on Leptin deficient mice, I would have never discovered or understood my genetic mutation.
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