An international team led by ICREA professor Aurora Pujol, a researcher at the Bellvitge Biomedical Research Institute (IDIBELL) and leader of the Neurometabolic Diseases group, has identified mutations in the RPS6KC1 gene as the cause of a new genetic neurodevelopmental disease. The discovery, recently published in the American Journal of Human Genetics, has been possible thanks to genome sequencing and the application of new clinical genomics tools and computational algorithms developed by the IDIBELL team.
The mutations have been detected in 13 people from 8 families around the world, who are not related to each other. One of the cases corresponds to a patient treated at the Bellvitge University Hospital, followed by Dr. Valentina Vélez de Santamaría, a neurologist at the centre and co-author of the study.
Research centres and hospitals from all over the world (Spain, the United States, Italy, Germany, the United Kingdom, Iran, Finland, Estonia, Pakistan, and Turkey) have participated in the research in an international collaborative effort.
From genetics to the clinic: a wide range of manifestations
Alterations in the RPS6KC1 gene result in a very heterogeneous clinical presentation. The clinical variety of the disease is so diverse that no clear relationship can be established between the genotype (the genetic mutation) and the phenotype (the expression of the genotype, the observable external appearance).
The neurological manifestations of the disease cover a broad spectrum of neurological impairment, ranging from severe congenital forms incompatible with life, to spastic paraplegia with severe or mild neurodevelopmental problems. Even some patients may have only a cognitive or behavioral disorder without motor impairment. However, it has been seen that most of the patients in the study share clinical manifestations with patients with Coffin-Lowry syndrome, establishing a parallelism between the two diseases. Coffin-Lowry syndrome is a rare genetic disorder, caused by mutation in another member of the same family as RPS6KC1 (in this case, the RPS6KA3 gene), and is characterized by growth abnormalities, dysmorphology, and intellectual disability ranging from mild to severe.
The comfort of a diagnosis: putting a name and surname to the disease
Identifying the gene responsible for a rare disease that has not yet been named is a major step forward, opening the door to future research that delves deeper into the study of RPS6KC1 and its functions. “Knowing the gene and how it works in the healthy body is key to understanding what goes wrong when it is mutated, and knowing it puts us one step closer to finding effective therapeutic strategies for patients with this disease,” says Dr. Pujol, director of the study, medical geneticist, and leader of the Neurometabolic Diseases research group at IDIBELL. “Also, putting a name and surname to the gene responsible for this new disease allows us to give a genetic diagnosis to patients who had not had a clear answer for years, in this case more than 10, and that is very gratifying,” adds Dr. Valentina Vélez de Santamaría, the neurologist at Bellvitge Hospital who has followed the Spanish patient, whose family was very involved and collaborative.
“Programs to improve the diagnosis of patients who did not have one until now, such as IMPaCT Genomics, bring us closer to a fairer and more egalitarian society. Although there are very few patients affected by diseases like this in the world, their families have the same right to quality healthcare as the rest of us. And diagnosis is the first step. Also, these types of discoveries advance scientific knowledge, since they greatly facilitate the understanding of fundamental mechanisms of brain functioning, which can help to better understand and treat both rare and more frequent diseases,” says Dr. Pujol.
RPS6KC1, a gene still little known
The gene RPS6KC1 codifies for a homonymous protein that is part of a large protein family, the RSK family. The additional cases to the Bellvitge Hospital patient, with whom they share mutations in this gene, have been identified thanks to GeneMatcher, an online platform that connects clinicians and researchers from all over the world to accelerate the discovery of new diseases.
There is still much to be discovered about RPS6KC1 and its specific functions, but it is known that RSK proteins have an essential role in cell growth, proliferation and the regulation of protein synthesis, as well as a prominent role in neurodevelopment. In addition, they are also closely linked to the biogenesis of ribosomes, the organelles that read genetic information and translate it into proteins.
To try to better understand what RPS6KC1 participates in, researchers have studied the impact of its mutations through the analysis of skin biopsies from patients and the study of experimental models with the same genetic alteration. From what they have seen, these mutations directly affect protein synthesis and lipid metabolism, as well as cause a decrease in ribosome abundance.
This research, an example of the value of joint work between biomedical research and the healthcare clinic at the Bellvitge Health Campus, has been financed by public funds from the Carlos III Health Institute, by the IMPaCT Genomics program and by funds from the TV3 Marathon of Rare Diseases. “I can’t think of a better use of public funds than this type of project, where we respond to patients who have been waiting for more than 10 years and at the same time contribute to the advancement of science on how the brain works,” concludes Dr. Pujol.
The Bellvitge Biomedical Research Institute (IDIBELL) is a research centre created in 2004 and specialising in cancer, neuroscience, translational medicine and regenerative medicine. It has a team of more than 1,500 professionals who, from 73 research groups, publish more than 1,400 scientific articles a year. L’IDIBELL is participated by the Bellvitge University Hospital and the Viladecans Hospital of the Catalan Health Institute, the Catalan Institute of Oncology, the University of Barcelona and the City Council of L’Hospitalet de Llobregat.
IDIBELL is a member of the Campus d’Excelencia Internacional of the University of Barcelona HUBc and is part of the CERCA institution of the Generalitat de Catalunya. In 2009 it became one of the first five Spanish research centres accredited as a health research institute by the Carlos III Health Institute. In addition, it is part of the HR Excellence in Research program of the European Union and is a member of EATRIS and REGIC. Since 2018, IDIBELL has been an Accredited Centre of the AECC Scientific Foundation (FCAECC).