July 23, 2025 • 17 mins
🎙️ Episode 84: Variants in NR6A1 cause a novel oculo-vertebral-renal syndrome
🧬 In this episode of PaperCast Base by Base, we explore the discovery of rare variants in the orphan nuclear receptor gene NR6A1 as the genetic cause of a newly described autosomal dominant oculo-vertebral-renal (OVR) syndrome characterized by colobomatous microphthalmia, vertebral anomalies, and congenital kidney abnormalities.
🔍 Study Highlights:
We performed genome sequencing in six independent families affected by uveal coloboma with or without microphthalmia and identified six rare NR6A1 variants segregating with disease. Functional validation included in silico modeling predicting disrupted DNA binding and ligand domain interactions, cellular assays showing mislocalization of mutant NR6A1 isoforms, and zebrafish morpholino knockdown experiments demonstrating eye, kidney, and somite developmental defects. Rescue experiments in zebrafish confirmed that wild-type human NR6A1 mRNA restored normal development while pathogenic variants failed to rescue these phenotypes.
🧠 Conclusion:
This study establishes NR6A1 as a critical pleiotropic regulator of eye, vertebral, and renal development, expanding the molecular diagnostic framework for coloboma and related syndromes and opening paths for future functional and therapeutic research.
📖 Reference:
Neelathi UM, Ullah E, George A, Maftei MI, Boobalan E, Sanchez-Mendoza D, Adams C, McGaughey D, Sergeev YV, AI Rawi R, Naik A, Bender C, Maumenee IH, Michaelides M, Tan TG, Lin S, Villasmil R, Blain D, Hufnagel RB, Arno G, Young RM, Guan B & Brooks BP. Variants in NR6A1 cause a novel oculo-vertebral-renal syndrome. Nat Commun. 2025;16:6111. doi:10.1038/s41467-025-60574-y
📜 License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/
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Transcript
Episode Transcript
Available transcripts are automatically generated. Complete accuracy is not guaranteed.
(00:14):
Welcome to Base by Base, the paper cast that brings genomics
to you wherever you are. OK, so imagine this a condition
that messes with your eyes, yourspine, and your kidneys all at
the same time. Sounds pretty complex, right?
What if it all came down to justone tiny tweak in your genetic
code? It sounds like science fiction,
but it's a very real challenge. Exactly.
(00:35):
And for a lot of kids and their families, figuring out the why
behind it has been, well, incredibly frustrating.
We're talking about things like congenital eye problems,
colaboma specifically. That's where parts of the eye
just don't form correctly. It's actually a a major cause of
childhood blindness. And even when it seemed pretty
clear there was a genetic link pinpointing the actual cause,
(00:57):
Yeah, that's been tough. Families often didn't get a
precise diagnosis. Right.
So today we're digging into a really exciting discovery that
connects these dots, these seemingly separate symptoms.
It finally identifies a specificgene responsible.
And it makes you wonder, how could solving this kind of
mystery change how we diagnose these really complex multi
system conditions down the road?It's a fantastic question and
(01:20):
this work really does represent a significant step forward,
particularly in understanding human development.
So today we should definitely celebrate the work of a really
dedicated team from the NationalEye Institute at the NIH.
They had collaborators too, fromthe UCL Institute of
Ophthalmology, Columbia University, Moorfields Eye
Hospital and others. Their detailed research has well
(01:43):
really pushed forward our understanding of these tough
congenital malformations. OK, so let's set the scene a bit
more. What exactly was the scientific
problem they were tackling? You mentioned Cullaboma.
Right. So the specific issue is
cullabomatous microthalmia. It's a severe eye defect that
happens really early in development.
There's this thing called the optic fissure, basically a seam
(02:05):
in the developing eye, and if itdoesn't close up properly, well,
that's where the problems start.And this is part of a whole
range, right? Like microfalmia, where the eye
is too small. Exactly.
Microfalmia, small eye, or even ophthalmia where an eye is
missing altogether. Coloboma fits into that
spectrum. And you said it's a big cause of
childhood blindness, even thoughit's rare overall.
Yeah, it seems counterintuitive,but coloboma can account for up
(02:29):
to maybe 10% of childhood blindness cases.
And like we said, despite years of research, genetic testing
often came back inconclusive. The diagnostic yield, as we call
it, was disappointingly low, especially for cases that just
seem to be isolated eye problems.
It was a real puzzle. A needle in a haystack
situation, basically. Much.
(02:50):
But then researchers started seeing a pattern.
Something beyond just the eyes. Exactly.
They noticed that some patients with colaboma they also had
other issues like missing vertebrae in their spine or
kidney abnormalities they were born with.
It was this recurring combination of symptoms, but
without a known genetic 'cause just this clinical observation
hanging there. Until this study.
(03:11):
Right, this study finally shinesa light on the genetic basis for
that specific pattern, and now it has a name, OVR syndrome.
OVR, Ocular, vertebral, renal makes sense.
Eye, spine, Kidney. Precisely, it describes the
triad of affected systems perfectly.
So how did they track down the gene?
What was the approach? They used what's called a genome
first approach, which is really powerful here.
(03:34):
They started by doing genome sequencing on individuals from
six different families. Critically, these families all
had individuals showing that specific OVR combination the
eye, spine and kidney problems. So they were casting a wide net,
genetically speaking. Exactly looking for rare genetic
changes variants that might be the common thread linking these
(03:54):
seemingly unrelated conditions, Letting the genetics lead the
investigation? Really.
OK. So they find some candidates
through sequencing, but just finding a variant isn't enough,
right? You have to prove it actually
causes the problem. How did they build that case?
I gather they started with computer modeling in silico
stuff. That's right.
The first step after finding thecandidate variance was using
(04:17):
these sophisticated in silico tools, computer simulations.
These models help predict how those specific variants might
change the protein that the Deancodes for, like would it change
its shape? Would it affect how it binds to
DNA? So trying to predict the
molecular consequence. Exactly.
It gives you that first really strong hypothesis about what
(04:38):
might be going wrong at the protein level, sort of like a
molecular blueprint of the potential problem.
OK, computer predictions done. Then they move to the lab bench.
In vitro experiments in cells. Next step in vitro they use
human cells, specifically HEK 293 cells grown in culture and
here they could directly comparethe normal or wild type protein
(05:00):
with the mutant versions found in the patients.
What? Were they looking for how it
behaved inside the cell? Primarily where it ended up in
the cell, It's localization. This protein needs to get into
the cell nucleus to do its job regulating other genes.
So did the normal protein go to the nucleus?
And crucially, did the mutant proteins also go there, or were
they stuck somewhere else, like the cytoplasm?
(05:21):
Gotcha. And then the really cool part,
the zebrafish moving into a living system in vivo.
Why is zebrafish? Zebrafish are fantastic for
developmental biology. They develop externally, they're
transparent early on, and their development is surprisingly
similar to humans in many ways, especially for things like I
formation. So you can actually watch
development happen. And you can manipulate their
(05:43):
genes relatively easily. So the researchers could knock
down the zebrafish equivalent ofthe human gene they suspected.
To see if the fish developed similar problems like the eye
defects. Exactly.
Did knocking down the gene causeeye problems, spine issues?
Kidney problems in the fish mirroring the human OVR
syndrome. And then the clinch the rescue
(06:04):
experiments. Yes, that's the crucial
validation step. First they'd see if adding back
the normal human version of the gene could rescue the zebrafish.
Basically fix the defects causedby the knockdown, then the
critical test Could the mutant human versions of the gene, the
ones found in the patients, alsorescue the fish?
Then if they couldn't. That's incredibly strong
(06:26):
evidence that those specific patient variants are truly
pathogenic, that they're the cause of the problem.
This multi layered approach, computational, cellular and
whole Organism is really what gives the finding such weight.
It connects the genetic variant directly to the developmental
outcome. That is thorough.
OK, so with all that careful work, what was the big reveal?
(06:47):
What gene did they identify? The central discovery was
identifying 6 rare variants in agene called NR. 6A1.
It's an orphan nucleoreceptor. Orphan, meaning we didn't know
exactly what it did before. Sort of.
Its function wasn't fully characterized, especially in the
specific developmental context, and these NR 6A1 variants were
identified as the cause of this newly defined ocular vertebra
(07:10):
renal or OVR syndrome. And how is it inherited?
It's autosomal dominant, meaningyou only need one copy of the
altered gene to potentially develop this syndrome.
Only potentially. Right, and this is important.
It shows incomplete penetrance and variable expressivity,
meaning not everyone who inherits the variant will
actually show symptoms. Or they might show only some of
the symptoms, and the severity can vary a lot, even between
(07:33):
people in the same family carrying the exact same variant.
Genetics is rarely spit forward.Wow, so how did this actually
look in the families they studied?
What were the specific clinical findings that linked back to NR
6A1? The evidence across the families
was really striking and consistent.
For example, in one family they found a deletion within the NR.
6A1 gene and the affected individuals had a bilateral
(07:58):
uveal colobomas, that's colobomaaffecting a specific part of the
eye plus missing vertebrae and one person was missing a kidney.
Unilateral renal genesis. OK, the classic triad.
Exactly. Then another family had a
different type of mutation, a point mutation in an NR. 6A1 and
again, bilateral colobomas, microfommia, missing left kidney
and even fewer thoracic vertebrae only 10 instead of the
(08:20):
usual 12. 10 instead of 12. That's significant.
It is, and a third family showedsimilar eye issues, colbomatous
microfolameria plus cataracts and spinal calcification, also
linked to an NR 6A1 variant. And this wasn't just in those
initial families, right? They found more cases.
Correct. They found additional supporting
cases through the UK's 100,000 Genomes project, which
specifically corroborated the eye abnormalities linked to NR
(08:43):
6A1. It really solidified the genes
role. OK, let's get back to the
molecular level. You said NR 6A1 is a nuclear
receptor. What's its day job supposed to
be and how did the variance messthat up?
Right. So as a nuclear receptor, it's
basically a transcription factor.
Its main job is to bind to DNA inside the nucleus and control
whether other genes are turned on or off.
(09:05):
It's a regulator. Like a switch?
A switch or maybe a dimmer, and the computer modeling predicted
that some of these variants, like the ones called R92 W and
R43D6C, would either stop the protein from binding to DNA
properly or make it fold up incorrectly.
And the cell experiments confirmthis.
Dramatically so. The normal NR 6A1 protein, as
(09:25):
expected, went straight to the nucleus, but the R436C mutant
protein, it was found almost entirely out in the cytoplasm.
Step outside the control. Room.
Exactly. It couldn't get into the nucleus
to do its job. It's like having to keep it
being locked out of the building.
The other variant, R 92 W, did make it to the Nucleus, but
tests showed its function was impaired, so even subtle changes
cause major problems. That makes sense.
(09:46):
And developmentally, when and where is NR 6A1 usually active?
Does that timing fit with the problems seen in OVR syndrome?
Spot on. The gene expression data shows
NR. 6A1 is most active in human embryonic stem cells and in
fetal tissues during really critical developmental windows.
And crucially, this includes theexact time period when that
(10:07):
optic fissure is supposed to close in the developing eye.
Perfect timing to cause colabomaif something goes wrong.
Precisely, and it's expression pattern also overlaps
significantly with other genes we already know 'cause colaboma
or kidney problems. It suggests NR. 6A1 is part of a
larger network controlling the development of multiple organ
systems, like a key player coordinating different sections
(10:28):
of the developmental orchestra. Which brings us back to the
zebrafish. When they knocked down NR. 6A1
in the SUS, what exactly did they see?
Did it really mimic the human syndrome?
The results were quite compelling.
When they reduce the function ofthe NR 6A1 gene or its
equivalence in zebrafish, the fish developed clear eye
problems, microfalmia, colaboma,just like the human patients.
(10:48):
But it wasn't just the eyes. They also saw things like heart
edema, problems with the body axis formation, and importantly,
kidney defects. They can even measure abnormal
expression of genes known to be critical for kidney development.
And the vertebrae. Yes, the vertebral defects were
there too. They look at Sumites, which are
the precursor structures that eventually form the vertebrae in
(11:10):
the affected fish. These Semites were malformed and
there were fewer of them. It really mirrored the human OVR
picture remarkably well. OK, so the knockdown mimicked
the syndrome. How did they use the rescue
experiments to absolutely nail that the human patient variants
were the culprit? Right, this was key.
First, they showed that injecting normal human NR. 6A1
(11:31):
genetic material mRNA into the affected fish embryos could
partially fix those defects. It could rescue the phenotype
proving the genes role. OK, so the normal human gene
works in fish. Yes, but then they injected mRNA
containing those specific patient variants like R 92 W or
R432C and those versions failed to significantly rescue the
(11:52):
fish. They couldn't fix the problems.
Exactly which is direct functional proof that these
specific alterations found in patients are indeed harmful.
They're pathogenic. They disrupt the genes function
in a way that causes these developmental issues.
And there was something about dosage sensitivity too.
Too much is also bad. That was another fascinating
finding. They found that overexpressing
(12:14):
normal NR. 6A1 in the zebrafish,giving them too much of the good
stuff, also cause developmental problems, including eye and
vertebral defects similar to theknockdown.
So it's a Goldilocks situation. The amount has to be just right.
Precisely, it highlights that normal development is incredibly
sensitive to the precise level the dosage of NR 6A1.
(12:36):
Too little causes OVR syndrome, but too much is also disruptive.
The balance is critical. Incredible.
So pulling this all together, what are the big implications?
What does this mean for patients?
For families? For research?
Well, first and foremost, it's agame changer for diagnosis.
This study firmly establishes NR6A1 as a pleotropic gene.
Meaning 1 gene affecting multiple different things.
(12:56):
Exactly, and it definitively links variants in this one gene
to OVR syndrome. This provides A molecular
diagnosis for actually a noticeable percentage, around
1.3 to 1.4% of previously unexplained cases in two large
groups of patients. That might sound small, but for
those families. Oh, for those families who've
been on a diagnostic odyssey, sometimes for years, finally
(13:19):
getting a specific genetic cancer, that's huge.
That provides clarity ends the uncertainty.
And clinically, what changes now?
Well, for any family presenting with colaboma, especially if
there are hints of spinal or kidney issues, testing for NR
6A1 variants should now be strongly considered.
Getting that genetic diagnosis early can really improve genetic
counseling. It helps families understand
(13:40):
inheritance patterns, recurrencerisks.
And potentially allows for earlier screening for associated
problems like the kidney issues.Absolutely critical kidney
problems might not be obvious atbirth, so knowing a child has an
NR 6A1, the variant prompts proactive screening, which could
lead to much earlier intervention if needed.
It also really underscores the need for thorough clinical
(14:01):
exams. Because of that variable
expressivity we mentioned, some people with the variant might
have only mild eye issues or maybe no obvious kidney
problems. Initially, you need to look
carefully at all three systems. Eyes, spine, kidneys.
So it encourages a more holisticview of the patient?
Definitely. And this finding doesn't exist
in a vacuum, right? Other groups were finding
(14:22):
similar links. Yes, that's another important
point. Around the same time, other
independent studies were also reporting NR 6A1 variants in
patients with kidney and vertebral problems.
Finding the same gene implicatedby different groups really
strengthens the evidence and confirms its crucial role across
these different developmental systems.
Are there still unanswered questions?
Other potential effects of NR6A1variants.
(14:45):
Oh, absolutely. While this study nails the link
to eyes, vertebrae and kidneys, some animal models suggested
potential links to other things,like intellectual disability or
maybe heart defects. Whether these are also features
in humans with NR 6A1 variants needs more investigation.
Human syndromes are complex and we need more patient data.
(15:06):
And future research will dig deeper into the how.
For sure, we need to understand the precise molecular
mechanisms. How does NR 6A1 dosage control
development? What other genes does it
interact with? There's particular interest in
its potential connection to pathways like retinoic acid
signaling, which we know is important for both eye and
kidney development. There's still lots to explore
(15:27):
there. It really showcases the power of
that genome first approach, doesn't it?
Starting with the genes to connect clinical dots that might
otherwise seem unrelated. It really does.
It's like finding the master keythat unlocks the understanding
of a complex syndrome involving multiple, seemingly disparate
parts. OK, so to it all down, what's
the main take home message here?I'd say the core message is that
this research identifies the NR 6A1 gene as a really critical
(15:51):
player in human development, specifically orchestrating the
formation of our eyes, vertebraeand kidneys.
Variants or mutations in the single gene are now known to
cause OVR syndrome. This provides vital answers for
affected families and truly highlights how powerful genomic
studies are for unraveling thesecomplex congenital conditions.
So what does this mean for you, listening to this?
Well, think about how discoveries like this one are
(16:13):
constantly refining our map of genetic disorders.
They open doors to more precise diagnosis, better counseling,
and hopefully down the line, more targeted ways to help
manage these complex developmental conditions.
It's a reminder that we're stilluncovering the fundamental
blueprints of human health, baseby base.
This episode was based on an Open Access article under the
(16:33):
CCBY 4 Point O license. You can find a direct link to
the paper and the license in ourepisode description.
If you enjoyed this analysis, the best way to support Base by
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show. Thanks for listening and join us
next time as we explore more science base by base.
Welcome to Base by Base, the paper cast that brings genomics
to you wherever you are. OK, so imagine this a condition
that messes with your eyes, yourspine, and your kidneys all at
the same time. Sounds pretty complex, right?
What if it all came down to justone tiny tweak in your genetic
code? It sounds like science fiction,
but it's a very real challenge. Exactly.
(00:35):
And for a lot of kids and their families, figuring out the why
behind it has been, well, incredibly frustrating.
We're talking about things like congenital eye problems,
colaboma specifically. That's where parts of the eye
just don't form correctly. It's actually a a major cause of
childhood blindness. And even when it seemed pretty
clear there was a genetic link pinpointing the actual cause,
(00:57):
Yeah, that's been tough. Families often didn't get a
precise diagnosis. Right.
So today we're digging into a really exciting discovery that
connects these dots, these seemingly separate symptoms.
It finally identifies a specificgene responsible.
And it makes you wonder, how could solving this kind of
mystery change how we diagnose these really complex multi
system conditions down the road?It's a fantastic question and
(01:20):
this work really does represent a significant step forward,
particularly in understanding human development.
So today we should definitely celebrate the work of a really
dedicated team from the NationalEye Institute at the NIH.
They had collaborators too, fromthe UCL Institute of
Ophthalmology, Columbia University, Moorfields Eye
Hospital and others. Their detailed research has well
(01:43):
really pushed forward our understanding of these tough
congenital malformations. OK, so let's set the scene a bit
more. What exactly was the scientific
problem they were tackling? You mentioned Cullaboma.
Right. So the specific issue is
cullabomatous microthalmia. It's a severe eye defect that
happens really early in development.
There's this thing called the optic fissure, basically a seam
(02:05):
in the developing eye, and if itdoesn't close up properly, well,
that's where the problems start.And this is part of a whole
range, right? Like microfalmia, where the eye
is too small. Exactly.
Microfalmia, small eye, or even ophthalmia where an eye is
missing altogether. Coloboma fits into that
spectrum. And you said it's a big cause of
childhood blindness, even thoughit's rare overall.
Yeah, it seems counterintuitive,but coloboma can account for up
(02:29):
to maybe 10% of childhood blindness cases.
And like we said, despite years of research, genetic testing
often came back inconclusive. The diagnostic yield, as we call
it, was disappointingly low, especially for cases that just
seem to be isolated eye problems.
It was a real puzzle. A needle in a haystack
situation, basically. Much.
(02:50):
But then researchers started seeing a pattern.
Something beyond just the eyes. Exactly.
They noticed that some patients with colaboma they also had
other issues like missing vertebrae in their spine or
kidney abnormalities they were born with.
It was this recurring combination of symptoms, but
without a known genetic 'cause just this clinical observation
hanging there. Until this study.
(03:11):
Right, this study finally shinesa light on the genetic basis for
that specific pattern, and now it has a name, OVR syndrome.
OVR, Ocular, vertebral, renal makes sense.
Eye, spine, Kidney. Precisely, it describes the
triad of affected systems perfectly.
So how did they track down the gene?
What was the approach? They used what's called a genome
first approach, which is really powerful here.
(03:34):
They started by doing genome sequencing on individuals from
six different families. Critically, these families all
had individuals showing that specific OVR combination the
eye, spine and kidney problems. So they were casting a wide net,
genetically speaking. Exactly looking for rare genetic
changes variants that might be the common thread linking these
(03:54):
seemingly unrelated conditions, Letting the genetics lead the
investigation? Really.
OK. So they find some candidates
through sequencing, but just finding a variant isn't enough,
right? You have to prove it actually
causes the problem. How did they build that case?
I gather they started with computer modeling in silico
stuff. That's right.
The first step after finding thecandidate variance was using
(04:17):
these sophisticated in silico tools, computer simulations.
These models help predict how those specific variants might
change the protein that the Deancodes for, like would it change
its shape? Would it affect how it binds to
DNA? So trying to predict the
molecular consequence. Exactly.
It gives you that first really strong hypothesis about what
(04:38):
might be going wrong at the protein level, sort of like a
molecular blueprint of the potential problem.
OK, computer predictions done. Then they move to the lab bench.
In vitro experiments in cells. Next step in vitro they use
human cells, specifically HEK 293 cells grown in culture and
here they could directly comparethe normal or wild type protein
(05:00):
with the mutant versions found in the patients.
What? Were they looking for how it
behaved inside the cell? Primarily where it ended up in
the cell, It's localization. This protein needs to get into
the cell nucleus to do its job regulating other genes.
So did the normal protein go to the nucleus?
And crucially, did the mutant proteins also go there, or were
they stuck somewhere else, like the cytoplasm?
(05:21):
Gotcha. And then the really cool part,
the zebrafish moving into a living system in vivo.
Why is zebrafish? Zebrafish are fantastic for
developmental biology. They develop externally, they're
transparent early on, and their development is surprisingly
similar to humans in many ways, especially for things like I
formation. So you can actually watch
development happen. And you can manipulate their
(05:43):
genes relatively easily. So the researchers could knock
down the zebrafish equivalent ofthe human gene they suspected.
To see if the fish developed similar problems like the eye
defects. Exactly.
Did knocking down the gene causeeye problems, spine issues?
Kidney problems in the fish mirroring the human OVR
syndrome. And then the clinch the rescue
(06:04):
experiments. Yes, that's the crucial
validation step. First they'd see if adding back
the normal human version of the gene could rescue the zebrafish.
Basically fix the defects causedby the knockdown, then the
critical test Could the mutant human versions of the gene, the
ones found in the patients, alsorescue the fish?
Then if they couldn't. That's incredibly strong
(06:26):
evidence that those specific patient variants are truly
pathogenic, that they're the cause of the problem.
This multi layered approach, computational, cellular and
whole Organism is really what gives the finding such weight.
It connects the genetic variant directly to the developmental
outcome. That is thorough.
OK, so with all that careful work, what was the big reveal?
(06:47):
What gene did they identify? The central discovery was
identifying 6 rare variants in agene called NR. 6A1.
It's an orphan nucleoreceptor. Orphan, meaning we didn't know
exactly what it did before. Sort of.
Its function wasn't fully characterized, especially in the
specific developmental context, and these NR 6A1 variants were
identified as the cause of this newly defined ocular vertebra
(07:10):
renal or OVR syndrome. And how is it inherited?
It's autosomal dominant, meaningyou only need one copy of the
altered gene to potentially develop this syndrome.
Only potentially. Right, and this is important.
It shows incomplete penetrance and variable expressivity,
meaning not everyone who inherits the variant will
actually show symptoms. Or they might show only some of
the symptoms, and the severity can vary a lot, even between
(07:33):
people in the same family carrying the exact same variant.
Genetics is rarely spit forward.Wow, so how did this actually
look in the families they studied?
What were the specific clinical findings that linked back to NR
6A1? The evidence across the families
was really striking and consistent.
For example, in one family they found a deletion within the NR.
6A1 gene and the affected individuals had a bilateral
(07:58):
uveal colobomas, that's colobomaaffecting a specific part of the
eye plus missing vertebrae and one person was missing a kidney.
Unilateral renal genesis. OK, the classic triad.
Exactly. Then another family had a
different type of mutation, a point mutation in an NR. 6A1 and
again, bilateral colobomas, microfommia, missing left kidney
and even fewer thoracic vertebrae only 10 instead of the
(08:20):
usual 12. 10 instead of 12. That's significant.
It is, and a third family showedsimilar eye issues, colbomatous
microfolameria plus cataracts and spinal calcification, also
linked to an NR 6A1 variant. And this wasn't just in those
initial families, right? They found more cases.
Correct. They found additional supporting
cases through the UK's 100,000 Genomes project, which
specifically corroborated the eye abnormalities linked to NR
(08:43):
6A1. It really solidified the genes
role. OK, let's get back to the
molecular level. You said NR 6A1 is a nuclear
receptor. What's its day job supposed to
be and how did the variance messthat up?
Right. So as a nuclear receptor, it's
basically a transcription factor.
Its main job is to bind to DNA inside the nucleus and control
whether other genes are turned on or off.
(09:05):
It's a regulator. Like a switch?
A switch or maybe a dimmer, and the computer modeling predicted
that some of these variants, like the ones called R92 W and
R43D6C, would either stop the protein from binding to DNA
properly or make it fold up incorrectly.
And the cell experiments confirmthis.
Dramatically so. The normal NR 6A1 protein, as
(09:25):
expected, went straight to the nucleus, but the R436C mutant
protein, it was found almost entirely out in the cytoplasm.
Step outside the control. Room.
Exactly. It couldn't get into the nucleus
to do its job. It's like having to keep it
being locked out of the building.
The other variant, R 92 W, did make it to the Nucleus, but
tests showed its function was impaired, so even subtle changes
cause major problems. That makes sense.
(09:46):
And developmentally, when and where is NR 6A1 usually active?
Does that timing fit with the problems seen in OVR syndrome?
Spot on. The gene expression data shows
NR. 6A1 is most active in human embryonic stem cells and in
fetal tissues during really critical developmental windows.
And crucially, this includes theexact time period when that
(10:07):
optic fissure is supposed to close in the developing eye.
Perfect timing to cause colabomaif something goes wrong.
Precisely, and it's expression pattern also overlaps
significantly with other genes we already know 'cause colaboma
or kidney problems. It suggests NR. 6A1 is part of a
larger network controlling the development of multiple organ
systems, like a key player coordinating different sections
(10:28):
of the developmental orchestra. Which brings us back to the
zebrafish. When they knocked down NR. 6A1
in the SUS, what exactly did they see?
Did it really mimic the human syndrome?
The results were quite compelling.
When they reduce the function ofthe NR 6A1 gene or its
equivalence in zebrafish, the fish developed clear eye
problems, microfalmia, colaboma,just like the human patients.
(10:48):
But it wasn't just the eyes. They also saw things like heart
edema, problems with the body axis formation, and importantly,
kidney defects. They can even measure abnormal
expression of genes known to be critical for kidney development.
And the vertebrae. Yes, the vertebral defects were
there too. They look at Sumites, which are
the precursor structures that eventually form the vertebrae in
(11:10):
the affected fish. These Semites were malformed and
there were fewer of them. It really mirrored the human OVR
picture remarkably well. OK, so the knockdown mimicked
the syndrome. How did they use the rescue
experiments to absolutely nail that the human patient variants
were the culprit? Right, this was key.
First, they showed that injecting normal human NR. 6A1
(11:31):
genetic material mRNA into the affected fish embryos could
partially fix those defects. It could rescue the phenotype
proving the genes role. OK, so the normal human gene
works in fish. Yes, but then they injected mRNA
containing those specific patient variants like R 92 W or
R432C and those versions failed to significantly rescue the
(11:52):
fish. They couldn't fix the problems.
Exactly which is direct functional proof that these
specific alterations found in patients are indeed harmful.
They're pathogenic. They disrupt the genes function
in a way that causes these developmental issues.
And there was something about dosage sensitivity too.
Too much is also bad. That was another fascinating
finding. They found that overexpressing
(12:14):
normal NR. 6A1 in the zebrafish,giving them too much of the good
stuff, also cause developmental problems, including eye and
vertebral defects similar to theknockdown.
So it's a Goldilocks situation. The amount has to be just right.
Precisely, it highlights that normal development is incredibly
sensitive to the precise level the dosage of NR 6A1.
(12:36):
Too little causes OVR syndrome, but too much is also disruptive.
The balance is critical. Incredible.
So pulling this all together, what are the big implications?
What does this mean for patients?
For families? For research?
Well, first and foremost, it's agame changer for diagnosis.
This study firmly establishes NR6A1 as a pleotropic gene.
Meaning 1 gene affecting multiple different things.
(12:56):
Exactly, and it definitively links variants in this one gene
to OVR syndrome. This provides A molecular
diagnosis for actually a noticeable percentage, around
1.3 to 1.4% of previously unexplained cases in two large
groups of patients. That might sound small, but for
those families. Oh, for those families who've
been on a diagnostic odyssey, sometimes for years, finally
(13:19):
getting a specific genetic cancer, that's huge.
That provides clarity ends the uncertainty.
And clinically, what changes now?
Well, for any family presenting with colaboma, especially if
there are hints of spinal or kidney issues, testing for NR
6A1 variants should now be strongly considered.
Getting that genetic diagnosis early can really improve genetic
counseling. It helps families understand
(13:40):
inheritance patterns, recurrencerisks.
And potentially allows for earlier screening for associated
problems like the kidney issues.Absolutely critical kidney
problems might not be obvious atbirth, so knowing a child has an
NR 6A1, the variant prompts proactive screening, which could
lead to much earlier intervention if needed.
It also really underscores the need for thorough clinical
(14:01):
exams. Because of that variable
expressivity we mentioned, some people with the variant might
have only mild eye issues or maybe no obvious kidney
problems. Initially, you need to look
carefully at all three systems. Eyes, spine, kidneys.
So it encourages a more holisticview of the patient?
Definitely. And this finding doesn't exist
in a vacuum, right? Other groups were finding
(14:22):
similar links. Yes, that's another important
point. Around the same time, other
independent studies were also reporting NR 6A1 variants in
patients with kidney and vertebral problems.
Finding the same gene implicatedby different groups really
strengthens the evidence and confirms its crucial role across
these different developmental systems.
Are there still unanswered questions?
Other potential effects of NR6A1variants.
(14:45):
Oh, absolutely. While this study nails the link
to eyes, vertebrae and kidneys, some animal models suggested
potential links to other things,like intellectual disability or
maybe heart defects. Whether these are also features
in humans with NR 6A1 variants needs more investigation.
Human syndromes are complex and we need more patient data.
(15:06):
And future research will dig deeper into the how.
For sure, we need to understand the precise molecular
mechanisms. How does NR 6A1 dosage control
development? What other genes does it
interact with? There's particular interest in
its potential connection to pathways like retinoic acid
signaling, which we know is important for both eye and
kidney development. There's still lots to explore
(15:27):
there. It really showcases the power of
that genome first approach, doesn't it?
Starting with the genes to connect clinical dots that might
otherwise seem unrelated. It really does.
It's like finding the master keythat unlocks the understanding
of a complex syndrome involving multiple, seemingly disparate
parts. OK, so to it all down, what's
the main take home message here?I'd say the core message is that
this research identifies the NR 6A1 gene as a really critical
(15:51):
player in human development, specifically orchestrating the
formation of our eyes, vertebraeand kidneys.
Variants or mutations in the single gene are now known to
cause OVR syndrome. This provides vital answers for
affected families and truly highlights how powerful genomic
studies are for unraveling thesecomplex congenital conditions.
So what does this mean for you, listening to this?
Well, think about how discoveries like this one are
(16:13):
constantly refining our map of genetic disorders.
They open doors to more precise diagnosis, better counseling,
and hopefully down the line, more targeted ways to help
manage these complex developmental conditions.
It's a reminder that we're stilluncovering the fundamental
blueprints of human health, baseby base.
This episode was based on an Open Access article under the
(16:33):
CCBY 4 Point O license. You can find a direct link to
the paper and the license in ourepisode description.
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