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“You can have too much of a good thing” is age-old wisdom
that applies to a lot of things: too much ice cream might give you a stomachache
and too much matter in one tiny space might give you a black hole.
And this principle can also apply to vitamin D.
If kids don’t get enough vitamin D, their bones won’t develop normally,
and they’ll get a disease called rickets.
But when countries started adding a lot of vitamin D to children’s food
to try to prevent rickets, doctors learned that some kids
also got sick from having too much vitamin D.
And figuring out why those kids got sick took decades.
And researchers had to solve the same problem twice.
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Getting to the bottom of this medical mystery is the second time that
a vitamin-D related illness has changed our understanding of disease.
But let’s start with the first: rickets.
The oldest known descriptions of rickets come from 17th-century England.
The disease is probably much older, but the Industrial Revolution
brought about changes that made children more susceptible.
Rickets often caused symptoms like delayed motor skills,
chronic pain, bowed legs, and flared wrists.
Fatal seizures and heart problems could also occur.
By the turn of the 20th century, scientists were after a cure.
The study of nutrition on a molecular level was just beginning,
and researchers knew that certain substances, dubbed vitamins,
could cause problems if they were absent from your diet.
So they went looking for one involved in rickets,
which led to the discovery of vitamin D.
Unlike vitamins A, B, and C, which had already been discovered,
they found that vitamin D was a little bit different.
It could come from food, sure.
Cod liver oil is a good source.
But they also knew that sunlight could cause the body to make vitamin D.
Yet just knowing the cause wasn’t enough to actually get
a balanced diet into people’s bellies, or score them beach vacations.
So putting vitamin D directly into infant formula seemed like
a great way to solve a huge, widespread public health problem.
But they might have gone a little overboard.
By the 1950s in Britain, fortification of infant formula and milk
led to infants getting up to 4,000 international units of vitamin D per day.
For comparison, the US Centers for Disease Control and Prevention today
recommends just 400 IU of vitamin D per day for infants under 1 year old,
and 600 IU for kids between 1 and 2 years old.
So 4,000 IU was wildly out of proportion with kids’ actual needs.
And between 1953 and 1955, Great Britain had 204 cases of infants
with dangerously high levels of calcium that they couldn’t quite explain,
beyond the associated increase in vitamin D in food.
Vitamin D helps the body create mineralized calcium,
which you need for bones and stuff.
With so much extra vitamin D in their system,
and no quick way for the body to get rid of it, too much calcium and phosphate
get absorbed into the bloodstream, which leads to
kidney problems and a host of other issues.
New regulations limited the amount of vitamin D that could go into fortified food,
and that reduced the number of cases.
But it took another 50 years for researchers to understand
who was susceptible, and why.
In 2011, researchers identified a mutation in a gene called CYP24A1.
A mutation in that gene stops the body from
breaking down excess vitamin D like it normally would.
And that led to those individuals being way more susceptible
to the kidney issues that result from too much vitamin D.
So that explains why trying to cure one disease causes another.
Mystery solved.
Well… maybe mystery 90% solved.
Further research showed that, of people with infant hypercalcemia,
about 10% don’t actually have that mutation.
And for a disease to be caused by a single, clear-cut genetic mutation
most of the time doesn’t make a lot of sense,
because where’s it coming from if it’s not coming from literally this one gene?
To understand that, it helps to understand what a gene is.
Genes are instructions for making proteins.
And proteins do everything in your body.
They pull your muscles, break down your food, and allow neurons to fire.
They’re so important that the DNA that doesn’t code directly for proteins
has historically been ignored as “junk DNA.”
After all, when there’s an error in the instructions for a protein,
it’s obvious how that can lead to disease.
If the instructions are wrong, the protein is wrong, and it won’t work.
If the error is somewhere else, meh.
But about ninety-eight percent of your genome does not code for proteins.
And it’s not just there for decoration.
For example, there are flags in the code on
either side of every gene that mark the beginning and end.
When a gene gets read to be turned into a protein,
those flags get read as well.
The resulting “message” is a molecule called messenger RNA.
And the flag on one end, the 3’ end,
affects the shape of the RNA molecule that’s created.
“Three prime” is just the name for the far end of a length of nucleic acid,
such as RNA, and it’s named that for chemistry reasons
that we’re not gonna get into.
The 3’ flag of this messenger RNA is the part that
seems to matter to the remaining 10% of people with hypercalcemia.
Think of a properly-folded messenger RNA like the best paper airplane,
designed for that perfect loop-de-loop path.
In this case, the path it travels will take its message
to the part of the cell where it can be turned into a protein.
The 3’ end holds the message in place while it’s being read.
When the 3’ end is mutated, the folds get all thrown off,
and the plane, or the mRNA, can’t do what it needs to do.
Researchers think there are two possible explanations:
either the mRNA has trouble moving through the cell,
or once it reaches the protein-making machinery, it just can’t hold still.
So the proteins come out with the wrong shape, or even in just the wrong place,
which means they’re not as good at their job:
regulating the level of vitamin D in your blood.
When researchers analyzed blood samples from 6 patients with
unexplained hypercalcemia, they found a lot of
misfolded mRNA, among other things.
The paper, published in 2023, showed that, in these patients, the protein-coding
part of the CYP24A1 gene was fine, so the diagnostic tests had missed them.
But mutations in the 3’ end of the gene meant that the mRNA was misfolded,
and the protein couldn’t do its job.
While it’s not the first time we’ve ever discovered that a mutation
in a non-coding region is directly connected to a disease,
it’s still pretty early for this kind of research.
It’s a demonstration that that 98% of DNA that
doesn’t get turned into protein really, directly matters in people’s lives.
And that’s just how wild and winding the path of research can be:
the study of one disease led to its cure, which led to the discovery of
a new disease, which led us to an entirely new framework
to think about genetic diseases.
And we owe it all to rickets, so thanks, I guess?
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