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Some Genetic Mutations May Offer Protection Against Developmental Disorders

Tel Aviv University researchers have made a remarkable discovery that could revolutionize our understanding of genetic mutations and their role in brain development. The study, published today in Genomic Psychiatry, reveals that not all genetic mutations are harmful – some may actually offer protection against developmental disorders.

Led by Professor Illana Gozes, Director, The Elton Laboratory for Molecular Neuroendocrinology, the research team identified a protective inherited mutation in the Activity-Dependent Neuroprotective Protein (ADNP) gene. This finding challenges the traditional view that genetic mutations in ADNP invariably lead to developmental challenges.

I was struck by how this particular mutation actually enhanced certain protein interactions, potentially offering protection against developmental disorders. This discovery opens up entirely new perspectives on how we view genetic variations and their impact on brain development."

Professor Illana Gozes, Director, The Elton Laboratory for Molecular Neuroendocrinology

The study focused on a unique case where a mother carrying an ADNP mutation showed above-average adaptive behavior, while her child, inheriting both this protective mutation and a second variant, demonstrated better outcomes than typically seen in similar cases.

Key findings include:

• The protective mutation (ADNP_Glu931Glyfs*12) creates an additional protein interaction site

• This enhancement leads to stronger cellular connections and improved protein function

• The discovery suggests potential new therapeutic approaches for neurodevelopmental disorders

What makes this finding particularly intriguing is how it might influence our approach to genetic therapy. Could other seemingly harmful mutations harbor unexpected benefits? How might this knowledge be applied to develop more effective treatments?

Dr. Shula Shazman, a co-author of the study, notes that their computational modeling revealed how this protective mutation strengthens crucial cellular processes. This insight raises interesting questions about the potential for identifying similar protective mutations in other genes associated with neurodevelopmental disorders.

The research has immediate implications for how we understand and treat ADNP syndrome, a rare genetic condition affecting brain development. More broadly, it challenges us to reconsider our assumptions about genetic mutations in neurodevelopmental disorders.

The study employed advanced computational modeling alongside clinical observations, led by the psychiatrist, Prof. Joseph Levine. The results demonstrated how modern bioinformatics can reveal unexpected benefits in genetic variations previously considered purely detrimental.

Looking ahead, this research opens several compelling avenues for further investigation: How common are protective mutations in other neurological conditions? Could this discovery lead to new therapeutic strategies for related disorders?

From bench to bedside, Professor Illana Gozes further serves as Vice President for Drug Development at Exonavis Therapeutics, developing the investigational drug davunetide, a neuroprotective fragment of ADNP, for the treatment of ADNP syndrome and related neurodevelopmental/ neurodegenerative disorders. Indeed, her original discoveries providing the basis for davunetide also stemmed from structure-function relations toward new horizons,

Source:

Journal reference:

Gozes, I., et al. (2024) Protective inherited mutations in activity-dependent neuroprotective protein (ADNP): the good, the bad, and the ugly, Genomic Psychiatry. DOI: 10.61373/gp024r.0079. https://url.Genomicpress.Com/45ek73de

Isolated Communities Are More At Risk Of Rare Genetic Diseases

ISLAND LIFE is famously idyllic, but it's long been known that islanders tend to experience disproportionately high rates of some rare genetically transmitted diseases. Faroe islanders, for example, who live on an archipelago in the North Atlantic Ocean, have a much higher-than-average incidence of carnitine transporter deficiency (CTD), a condition that prevents the body from using certain fats for energy. Inhabitants of Gran Canaria, meanwhile, an island off the north-western coast of Africa, are far more likely than average to have familial hypercholesterolaemia, a condition where the liver cannot process cholesterol effectively.

A new paper in Nature Communications provides one more such example. Jim Flett Wilson from the University of Edinburgh, who led the study, reports that people living on the Shetland Islands in northern Scotland have a one-in-41 chance of carrying the gene variant which causes Batten disease, a life-limiting neurodegenerative disease. The comparable rate elsewhere in Britain is one in 300, says Dr Wilson.

Such elevated risk is likely to be the consequence of genetic isolation. When members of a small population overwhelmingly reproduce with their fellows, the probability of children acquiring disease-causing mutations (known as variants) from their parents increases over time. This happens because of a process known as random genetic drift, says Dr Wilson, whereby some genetic variants become more common and others are lost. "This effect is magnified in small populations with little or no inward movement of new people to replenish the genetic pool," he says.

Such isolation need not only be the product of encircling water. Dr Wilson's new study also found "genetic islands" on the British mainland. In Lancashire, for example, the researchers found locals were more likely to have ten disease-causing variants—including one associated with Zellweger syndrome, a disease affecting the brain, liver and kidney which can be fatal in the first year of life. Those from the area were 73 times more likely to have the variant. In South Wales, one variant responsible for an inherited predisposition to develop kidney stones later in life was 44 times more common, whereas in Nottinghamshire a variant causing a severe blistering skin disorder was 65 times more common than elsewhere.

Such genetic islands can arise from geography and culture, says Dr Wilson, including a widely shared preference for individuals to pick spouses from the same community they grew up in. Some such islands are already monitored by health authorities. The NHS, for example, runs screening programmes for those of Ashkenazi Jewish descent, as around one in 40 Ashkenazi Jewish people carries harmful variants to the BRCA gene which make them more at risk of breast or ovarian cancer. This compares with around one in 260 people in the general British population.

The incidence of Batten-disease carriers among Shetland islanders is similar to that of the BRCA variant among Jews, says Dr Wilson, and yet no plans exist for a screening programme there. He says that the reliance on the "cascade" model, whereby people are offered testing only after a family member is diagnosed, is only half as reliable at picking up cases as universal testing on demand. Until such screening programmes are put in place, islanders risk being doubly isolated.

Customized CRISPR Treatments Could Help People With Rare Genetic Disorders

MARY LOUISE KELLY, HOST:

A gene-editing technique called CRISPR has started to revolutionize medicine. But for people born with one of thousands of very rare genetic disorders, the era of CRISPR is bittersweet. That is because their disorders are too rare to attract drug companies to develop a CRISPR cure for them. NPR health correspondent, Rob Stein, has the story of some researchers trying to change that.

ROB STEIN, BYLINE: Lucy Landman was born with a very rare genetic disorder. It causes severe intellectual disability, weak muscles, often seizures, sometimes autism. Lucy's now three. Her mom's name is Geri.

GERI LANDMAN: She's expected to, you know, very much never be able to live independently, likely never be potty trained, likely never speak. Lucy walks like she's drunk most of the time. It's hard to watch your child suffer. And Lucy does, some days, suffer a lot.

STEIN: There's only a handful of kids in the world with Lucy's disorder. It's called PGAP3-CDG. And currently, there's no way to treat it. In principle, CRISPR, which enables scientists to easily make very precise changes in genes, could be a godsend for Lucy. CRISPR can edit the pairs of genetic letters or bases that make up DNA.

LANDMAN: We're lucky that both of her mutations - the one that she gets from me and the one that she gets from my husband - are what we call base editable, right? You can use CRISPR to kind of cut out the wrong base pair and put back in the right one - and that we live in 2024 when that's a legitimate possibility.

STEIN: But Landman, who is also a pediatrician who lives outside San Francisco, says the disorder affects too few people to attract the millions of dollars necessary to find out.

LANDMAN: When Lucy was diagnosed, I asked a bunch of my kind of basic science friends - you know, who work at Genentech and all these other big companies in the Bay Area. And I said, who's kind of working on - like, can't we just CRISPR this? This seems like it's so feasible. And they were like, I don't know of anyone - anyone at all. It's, like, no one's working on this yet, Geri.

STEIN: But then one day, Landman bumped into a guy at a farmers' market where she was trying to raise money for a foundation she started to try to change that. His name was Fyodor Urnov. Urnov works at the University of California, Berkeley, with Jennifer Doudna, who shared a Nobel prize for helping discover CRISPR. Urnov knows CRISPR is already changing the lives of some patients with genetic disorders, but he's trying to help kids suffering from much rarer conditions.

FYODOR URNOV: The for-profit sector is focusing on conditions such as sickle-cell disease, such as cancer, which are commercially viable because there's just enough people with them. And that leaves, frankly, you know, 99.5% of folks outside of the big building that says come here, be healed by CRISPR, because the commercial viability is not there, even though the technical feasibility is right in our hands.

STEIN: So Urnov and scientists at other universities are trying to develop a kind of template for groups of rare conditions that are similar enough that a CRISPR treatment for one could easily be adapted for others.

URNOV: We're building a set of recipes and approaches for how to switch from one disease to another and not take four years and 10 million to do that.

STEIN: The approach from one patient to the next would be essentially identical except for the very specific genetic letters that are edited, so each case wouldn't necessarily have to go through a long, expensive approval process at the Food and Drug Administration.

URNOV: The central idea is that cookbook will have been reviewed by the Food and Drug Administration. And so you can come to them, whether you are at UCLA, Seattle Children, and then say, FDA, we have a severely ill child with four months to live. Here's the cookbook for how to make the CRISPR on demand. We'd like to use that cookbook. And the goal is for the FDA or any other regulatory agency to say, yes, we understand. Please proceed. That's the goal.

STEIN: Dr. Peter Marks, who regulates gene editing at the FDA, says it would be like approving a new shaving razor.

PETER MARKS: CRISPR is very much like a razor blade handle and a razor. Much of CRISPR - the razor blade handle part - is going to be the same over and over again. And so we just need to focus on the razor blade portion, which could be different and yet fit on that same razor.

STEIN: Urnov has already started editing some of Lucy Landman's cells in his lab to show that CRISPR could help her and other kids with similar mutations. Lucy's mom is hopeful that maybe, someday, that could help her daughter.

LANDMAN: And the question is, if we do that at age 3 or age 5 or age 7, can we cure some of the other features of her disease, you know? Does she cognitively improve? Does she learn to speak in that way? That's certainly the hope.

STEIN: For Lucy and millions of children around the world suffering from very rare genetic disorders.

Rob Stein, NPR News. Transcript provided by NPR, Copyright NPR.

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