Episode Transcript
[00:00:20] Welcome to Base by Bass, the papercast that brings genomics to you wherever you are. Thanks for listening and don't forget to follow and rate us in your podcast. Appreciate Base by Bass is now on YouTube too, at Base by Bass, where every episode gets a video with chapters and the full description. Come subscribe.
[00:00:44] Imagine two people who carry altered copies of the same gene. The first is a small child. In early childhood the child's face begins to change, the bones and joints are affected, the liver and spleen grow and the heart and lungs come under strain.
[00:01:01] Development slows. The second is an adult. In later life, joints, heart, lungs and mind all seem fine. The only problem is the eyes.
[00:01:12] Slowly, over years, the edges of vision have been closing in and dim light has become hard to see in.
[00:01:21] For a long time nobody would have connected those two people. The child would be seen by a metabolic specialist, the adult would be seen by an eye doctor Told the diagnosis is retinitis pigmentation pigmentosa, a slow inherited loss of the light sensing cells of the retina and sent for a test of retinal genes. Yet in this story the same gene sits behind both.
[00:01:44] How can one gene cause a disease that touches almost every organ in one person and seemingly only the eye in another?
[00:01:54] Here is one way to picture Inside every cell, small compartments called lysosomes act as a cleaning crew, breaking down worn out material so it can be recy.
[00:02:05] Now imagine that crew cut to a tiny fraction of its normal size. If the crew disappears completely, waste piles up everywhere and fast. But if a handful of workers remain, most rooms in the building stay more or less tidy. Only the busiest room, the one making the most mess every single day, starts to fall behind in the body. That busiest room maybe the retina. That is the idea at the heart of today's episode. A gene known for a severe body wide childhood disease turning up in adults whose main problem, and sometimes only problem, is their sight. And the question is a precise how much of the enzyme is left in these people? And could that small leftover amount be the difference between a sick body and a spared one foreign.
[00:03:01] Today we celebrate the work of Sai Ying Lin, Gavin Arno and colleagues from the University of Manchester, the UCL Institute of Ophthalmology, the Greenwood Genetics center and partner centers in Ireland, Italy, the Netherlands and the United States who have advanced our understanding of how a lysosomal disease gene can cause retinal disease.
[00:03:24] Their paper Hypomorphic idua genotypes are associated with retinitis pigmentosa in individuals without syndromic mucopolysaccharidosis type 1 was published in the American Journal of human genetics in November 2026.
[00:03:44] Let's start with the gene. IDUA carries the instructions for an enzyme called alpha luronidase. Its job is to break down two sugar chains, dermatan sulfate and heparan sulfate, inside the lysosome. These chains belong to a family called glycosaminoglycans, usually shortened to gags. When both copies of IDUA lose their function, the chains are only partly broken down, and they build up in tissue after tissue, I.e. mucopolysaccharidosis type 1 or MPS1, a recessive lysosomal storage disorder.
[00:04:23] MPS1 has classically been split into three forms. At the severe end is Hurler syndrome. Children present early with coarse facial features, skeletal changes, enlarged organs, hearing loss, heart and lung disease, and developmental delay, and without treatment, life expectancy is greatly reduced.
[00:04:44] At the attenuated end is SHY syndrome. Cognition and life expectancy are close to normal, but stiff joints, clouded corneas and heart valve disease usually appear in the first or second decade of life. Hurlerschai sits in between.
[00:04:59] In reality, the authors note, the spectrum is continuous.
[00:05:05] There is also a broad rule linking genes to severity. The milder forms are strongly associated with carrying at least one missense variant, a single letter change that swaps one amino acid in the enzyme rather than wiping it out. And the eye was already part of the classic picture. People with MPS1 can have clouded corneas, glaucoma, optic nerve problems and a pigmentary retinopathy. That retinopathy is thought to come from storage material building up in the support layer behind the photoreceptors and in the space around them.
[00:05:41] So retinal disease in MPS1 was not news.
[00:05:45] What was unclear is whether IDUA could cause retinitis pigmentosa almost on its own in adults with little or no other sign of the disease.
[00:05:55] Only a handful of such cases had been described.
[00:05:58] One was a 65 year old with retinal dystrophy and hearing loss but no other apparent systemic features.
[00:06:05] Another was an adult whose retinopathy, diagnosed at age 34, turned out to be the first sign of attenuated MPS1 scattered cases not yet a pattern.
[00:06:19] And there is a practical reason this matters. People with retinitis pigmentosa go to eye clinics, and eye clinics order panels of genes known to cause inherited retinal disease. A storage disorder gene may not be on that list. If it is missing, the diagnosis can be missed. And if it is found, a doctor faces a hard Question will this person go on to develop the rest of the disease or not.
[00:06:44] Answering that means knowing how well the enzyme still works.
[00:06:54] So who are the people in this study?
[00:06:56] 14 individuals from 12 families aged between 19 and 73 years.
[00:07:03] Every one of them first came to an ophthalmology study service with retinitis pigmentosa. They were recruited from inherited retinal disease cohorts in the United Kingdom, Ireland, Italy, the Netherlands, and the United States, and all had genome or exome sequencing.
[00:07:19] For each of them, changes in other known retinal disease genes had been ruled out, and two altered copies of IDUA were the only plausible explanation left.
[00:07:32] Finding two variants is only the start the team needed to know. They sat on opposite copies of the gene, where relatives were available. They followed how the variants traveled through the family where they were not. They read the phase directly from sequencing reads or inferred it from population data. They also screened for pseudo deficiency alleles, variants that lower the enzyme's activity in a lab test without causing disease and that can fool a diagnosis. In the 12 of 14 individuals screened, none was found.
[00:08:06] Then came the clinic. The eye workup included wide field photographs of the retina, autofluorescence imaging, optical coherence tomography and electroretinograms, which record the electrical response of the retina to flashes of light. Where possible, people were also assessed for systemic features of MPS1, and blood and urine were tested. The blood test measured enzyme activity in white blood cells. The urine test measured how much of those gag chains was spilling out of the body.
[00:08:38] The core of the lab work tested each variant on its own. The team used a human cell line in which IDUA had been knocked out, so it makes no enzyme of its own.
[00:08:49] Into these cells they put a copy of the gene carrying one variant at a time.
[00:08:54] Then they measured two how much enzyme activity came out and how much enzyme protein was there.
[00:09:00] Dividing one by the other gives the relative specific activity. The work done per unit of enzyme compared with the normal enzyme in our cleaning crew picture. That number asks how much cleaning each worker actually does. The team also looked at the enzyme protein itself itself on a western blot. This matters because the enzyme is trimmed into smaller forms once it reaches the lysosome. So a properly trimmed enzyme is a sign that it arrived in the right place. A variant can fail in different ways. The enzyme can be made but work poorly. It can be unstable or it can be made in low amounts. The blot helps tell these apart.
[00:09:44] Finally, for one puzzling variant, they went to the rna. They copied the IDUA message from a participant's sample and read it with nanopore long read sequencing, which reads each molecule from end to end.
[00:09:59] Because each read is long, it can be assigned to one copy of the gene or the other, using nearby single letter differences as tags that let them see what each copy was actually producing one message at a time.
[00:10:18] So what did they find?
[00:10:19] The first clue is in the genes themselves.
[00:10:22] No one in the cohort carried two null alleles, that is Two copies that make no working enzyme at all. Instead, most carried one copy predicted to lose function completely, paired with a missense variant on the other copy.
[00:10:38] In our crew picture, one copy sends no workers.
[00:10:41] Everything depends on the second copy and on how much work its workers can still do.
[00:10:49] Then the clinical picture retinitis pigmentosa or rod cone dystrophy was the presenting feature in all 14.
[00:10:57] The damage mostly hit the mid peripheral retina around the center and swelling at the macula was common.
[00:11:04] Nine individuals had comprehensive systemic evaluations. Of these, seven had no features consistent with MPS1 at their last assessment at ages from 46 to 73.
[00:11:16] So seven people with two altered copies of a gene for a multi system disease and no sign of it outside the eye.
[00:11:26] Even those who did have features of attenuated MPS1 started late.
[00:11:31] Their disease began somewhere between their 20s and their 50s, much later than is typical for either classical or attenuated forms. The retinal tests also carried signatures previously reported in metabolic retinopathies. In one individual the response of the rods to a very dim flash was undetectable and the response to a strong flash had a so called negative shape. The overall pattern was was that of rod cone dystrophy.
[00:12:01] Now the biochemistry enzyme activity in white blood cells was reduced in every individual tested, nine of them, but it was never abolished. Reduced, not absent. That is the central observation of the study. It suggests these variants are not acting through some special retinal version of the enzyme. The whole body has less enzyme and and the retina seems to be more vulnerable to having less urine GAG levels meanwhile were outside the normal range in only half of those tested and when raised only modestly.
[00:12:37] What about the variants one by one in the cell assay several missense variants showed a relative specific activity of roughly 0.5 to 1.5% of the normal enzyme.
[00:12:50] That range matches variants already known from attenuated MPS1, and a known attenuated variant tested for comparison fell in the same range on the blot. These same variants were poorly processed and showed low stability or expression. Each worker does about 100th of a normal shift, a tiny amount, but not zero.
[00:13:14] Not every result fit neatly. One variant produced an enzyme that was well expressed and processed like the normal one, yet showed no measurable activity at all.
[00:13:24] Another, a glycine to alanine change, looked close to normal in the assay for that one. The authors suspect the damage happens at the level of splicing, but no RNA sample was available, so the idea rests on prediction alone and a variant of uncertainty. Significance from a previously published case also looked near normal, suggesting it may not explain that person's disease.
[00:13:50] The most interesting puzzle was one recurrent variant. It turned up in six affected individuals each time paired with a known stop variant on the other copy. It is Rare, seen in 96 alleles out of more than one and a half million in a large population database.
[00:14:07] On paper it swaps a single amino acid, but in the cell assay, that swap caused no measurable loss of enzyme activity. So why would it cause disease? The clue was its position at the second to last letter of Exon 2, right where the cell cuts and joins the message.
[00:14:26] The long reads answered it in reads from the copy carrying the variant, 85.1% skipped Exon 2, entirely removing part of the enzyme's core structure. A similar deletion tested by the team left the enzyme with no detectable activity.
[00:14:43] Another 12.7% used a wrong splice site that shifts the reading frame, and just 1.3% 6 reads out of 456 were spliced normally 1.3% a trickle of message that makes enzyme with essentially normal activity.
[00:15:03] Put another way, most workers from this copy arrive without their tools, but one or two in every hundred arrive fully equipped and work at full speed. The authors propose that this trickle contributes to the low residual enzyme activity seen in these people.
[00:15:19] So three different lower activity per enzyme, poor processing and leaky splicing all lead to the same place. A small amount of working enzyme Low but not gone.
[00:15:37] Why would the retina fail? First, the authors offer a model. A low level of enzyme may be enough to avoid early multisystem disease, but the retina has an exceptionally high metabolic demand and may be especially vulnerable to even even modest drops in lysosomal function.
[00:15:54] Our busiest room, similar retina first or retina only forms have been reported for other storage disorder genes, including CLN3, MFSD8, SGSH, HGSNAT, and SUMF1. That suggests a pattern reaching beyond IDUA for clinics. The message is concrete.
[00:16:17] The authors argue that IDUA and other MPS genes with retinal features should be included in inherited retinal disease gene panels.
[00:16:27] When two IDUA variants turn up in someone with retinitis pigmentosa, white blood cell enzyme testing and urine gag analysis should be considered along with referral to metabolic specialists.
[00:16:39] But there is a Enzyme results can support a diagnosis, yet they cannot reliably predict how severe the disease will be.
[00:16:51] There is a therapeutic angle too. If a little enzyme protects the body but not the retina, treatments for MPS1 may face two different targets. Even modest restoration of the enzyme could bring systemic benefit, while higher and sustained activity may be needed to prevent one retinal degeneration. That is a suggestion the authors raise from these observations, not something this study tested.
[00:17:18] And then there is newborn screening. Several large programs now sequence the genomes of newborns and MPS1 is among their target disorders. Because it is treatable, these data add a complication. A baby could carry an IDUA genotype linked to little or no no early multisystem disease and instead to late retinal disease with no established treatment. How should that be handled? The authors say it remains unclear. Early detection might though open a window for emerging retinal therapies before much of the retina is lost.
[00:17:55] Now the limits. This is a small series of 14 people, mostly of European ancestry.
[00:18:02] Systemic assessment varied in depth from person to person and there was no long term follow up. So some of those classed as having retinal disease alone may still develop systemic features. The splicing mechanism was confirmed for one variant only, and what separates people who stay retina only from those who progress despite similar residual enzyme activity is not yet understood.
[00:18:31] So here is where this leaves us. Two Altered copies of IDUA do not always mean a child with a severe body wide disease. In 14 people they showed up first as retinitis pigmentosa and in seven of the nine fully assessed as nothing more. At last review different variants, different mechanisms, the same endpoint. A small amount of working enzyme, enough, it seems to spare most of the body. Apparently not enough for the retina.
[00:19:03] Remember our cleaning crew cut down to a handful of workers.
[00:19:08] Most of the building stays tidy while the busiest room quietly falls behind.
[00:19:13] If the retina is where a weakened lysosome shows itself first, what does this mean for the future future of eye clinics? And how many other storage diseases might be hiding behind a diagnosis of fading sight?
[00:19:31] This episode was based on an Open Access article under the CCBY 4.0 license. You can find a direct link to the paper and the license in our episode description. If you enjoyed this follow or subscribe in your podcast. Apply and leave a five star rating. If you'd like to support our work, use the donation link in the description. Thanks for listening and join us next time as we explore more science base by base.
