Where does ordinary genetic diversity between individuals end and pathology begin? Albinism, most often characterized by extremely light skin, hair, and eyes, gives the illusion of a condition that genetics could easily distinguish from a healthy person. Yet, one of its most frequent forms, due to the dysfunction of the OCA2 protein, turns out to represent the extreme end of the pigmentation range characteristic of our populations. The lower the level of functional OCA2, the lighter the pigmentation becomes… until it crosses a threshold known as pathogenicity, corresponding to albinism, concludes new research conducted within an Inserm unit in Bordeaux in collaboration with the medical genetics department of the Bordeaux University Hospital.
Albinism, a vision disorder
“ The OCA2 gene was initially named BEY for 'blue eyes' because it was discovered through one of its variants linked to blue eyes. The detection of this variant is, in fact, part of the arsenal developed by some countries to create genetic profiles in forensic science.", tells Science and Future geneticist Sophie Javerzat, who led this new research published in the journal PLOS GeneticsIn fact, the OCA2 protein is a pH regulator necessary for the production of pigment (melanin) in melanosomes. These small, pigment-specific factories orchestrate the color of our skin, hair, and eyes. However, albinism is not always identified by light pigmentation; indeed, some patients have brown hair or brown eyes. On the other hand, all patients exhibit a characteristic and more or less pronounced visual impairment linked to a pigmentation defect in their retina. This makes albinism one of the most frequent causes of congenital blindness." explains Sophie Javerzat.
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Thanks to data from more than 3,000 patients registered at the Bordeaux University Hospital and with the support of the patient association GenespoirResearchers have identified several rare variants of OCA2, meaning versions whose genetic code is altered compared to its standard sequence. The problem is that doctors don't know how these variants cause the disease, so people who carry them remain undiagnosed.
One less piece of footage
The answer, for some, lies in the process of synthesizing the OCA2 protein from the gene of the same name. One of the steps, called splicing, involves sorting the sequence fragments that code for the amino acids (the "building blocks") that make up the protein itself and the regulatory sequences that separate them. These latter sequences, called introns, are excised during the process, while the exons, carrying the coding sequences, are conserved and translated into proteins. But here's the thing: of the 24 exons that make up the OCA2 gene, number 10 was likely to be lost. These variants cause exon 10 to skip too frequently, without which the protein is not functional." explains Elina Mercier, first author of the publication. The more frequent this "skip" of exon 10 is, the less functional OCA2 there is, and the less pigment is produced.
A continuum from dark skin to light skin, all the way to albinism
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But, surprisingly, these discoveries are not limited to albinism. Everyone, and even some primates and other mammals, exhibits a low but existing level of exon 10 skipping.“,” reveals Sophie Javerzat. “Although it doesn’t function, this alternative OCA2 is still quietly passed down from generation to generation. And the more of it there is, the fairer the skin tends to be. This greater or lesser vulnerability to exon 10 skipping has undoubtedly been selected over the course of evolution to adjust vitamin D synthesis according to sunlight exposure,” scientists hypothesize.
Previously identified in dark-skinned populations, a common OCA2 variant responsible for an increased level of exon 10 skipping had until now gone unnoticed in light-skinned individuals, its effects being masked by other factors. It's a continuum: the proportion of this exon 10 skip could finely modulate pigment production across the entire skin color spectrum. And beyond a certain skipping threshold, albinism develops.", Elina Mercier sums up.
The question of defining the threshold of pathogenicity remains open.
The question then arises of the threshold. At what point can we conclude that albinism is present based on the skipping level of exon 10 of OCA2? That's a good question.“,” replies Sophie Javerzat. “The answer is all the more complex because this threshold probably varies from one person to another.” If one of the other proteins involved in melanin production is particularly efficient in you, perhaps this pathogenicity threshold will be higher than for another person."She illustrates this point. For example, a person from Southeast Asia, whose exon 10 skipping rate is often lower than in Europe, will have more leeway before crossing the pathological threshold." In the context of diagnosis, all of this is of great importance." adds Sophie Javerzat. Since our work began, several cases have been solved!“
Beyond the specific case of albinism, this new research offers a reflection on the still overly binary conception of rare genetic diseases. This is a paradigm shift, which also moves away from the Manichean concept that when a gene works you are healthy and when it doesn't, you are sick“,” reasons Sophie Javerzat. At the molecular level, nothing is ever that simple!“
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