RI-MUHC team builds a new model to study Nager and Rodriguez syndromes, revealing crucial information about the role of the SF3B4 gene
SOURCE: RI-MUHC
October 4, 2024
Nager and Rodriguez syndromes are rare but devastating genetic conditions. Tragically, many babies with severe forms of these disorders do not survive, while others may have serious skeletal, facial, and heart problems. However, new hope is emerging.
Researchers at the Research Institute of the McGill University Health Centre (RI-MUHC), led by Loydie Jerome-Majewska, PhD, have recently made a breakthrough in understanding the genetics behind these conditions. Their findings, published in PNAS, provide fresh insights that could lead to better treatments and outcomes for affected families.
Both Nager and Rodriguez syndromes are caused by pathogenic variants in the same gene, called SF3B4. This gene is crucial in creating the building blocks that cells use to make proteins; however, until now it has been challenging to understand how mutations in SF3B4 contribute to embryonic development and to these rare conditions.
“Understanding the role of the Sf3b4 gene in Nager and Rodriguez syndromes is vital as it provides insights into the underlying mechanisms that cause these severe congenital disorders, explains Jerome-Majewska, a senior scientist in the Child Health and Human Development Program at the RI-MUHC. “Our research not only advances our understanding of the fundamental processes involved in embryonic development, but also opens the door to potential therapeutic approaches. By identifying the specific genes and developmental events that are disrupted, we can explore targeted interventions that may one day prevent or mitigate these syndromes.”
Building a new model
The research team focussed on a specialised group of cells called neural crest cells, which are essential for facial development. They developed a novel mouse model of Nager and Rodriguez syndromes by specifically deleting the Sf3b4 gene in neural crest cells. This model, which mimics the human conditions, allowed the researchers to investigate the genetic abnormalities seen in patients.
"A gene is like a set of instructions to build a protein,” explained Jerome-Majewska. “When a cell reads these instructions, it first makes a rough draft, called pre-mRNA, which includes extra pieces of information that aren't needed. A process called splicing cuts out the unnecessary parts (introns) and puts together the important parts (exons) to create a final, clean version of instructions, the mRNA. We know that the Sf3b4 gene is crucial in the splicing process, but we wanted to learn more about how mutations in Sf3b4 disrupt it and impact fetal development."
While previous studies have used other model organisms such as Xenopus, zebrafish and mice, none have replicated the full spectrum of these disorders as accurately as this new mouse model. It uniquely mirrored many of the craniofacial skeletal defects observed in human patients, allowing the team to study how disruptions in splicing lead to the skeletal, facial, and cardiac abnormalities associated with the syndromes.
“The initial model we generated didn’t fully capture the craniofacial abnormalities we were aiming to study, which was disappointing,” said Shruti Kumar, PhD, who led the comprehensive characterization of the new model during her PhD training with Loydie Jerome-Majewska. “However, we persisted, refining the model by specifically targeting the neural crest cells, which are crucial for facial development. This led to a breakthrough, and when we saw how well our new model worked, it was a huge moment for us. Everyone in the lab was celebrating!”
New findings come to light
The research team shared several key findings in their publication. First, they showed that loss of Sf3b4 impaired both the generation and the survival of neural crest cells and disrupted the expression and splicing of several other genes — particularly those involved in facial and heart development.
This study is the first to uncover the involvement of histone modifiers — molecules that regulate gene activity — and identify patterns in the disrupted genes and splicing events. For example, the affected introns had a shorter length and T-rich region around the branch point. These insights offer a deeper understanding of the molecular mechanisms underlying Nager and Rodriguez syndromes.
“Clinicians and geneticists managing patients with these syndromes will benefit from a better understanding of the disease mechanisms, potentially leading to improved diagnostic tools and treatments,” says Jerome-Majewska. “Moreover, this research could also inspire further investigation into other splicing-related disorders, broadening its impact beyond just these two syndromes. In the long term, families affected by these rare conditions could see advancements in care, ultimately improving outcomes and quality of life for patients.”
The researchers gratefully acknowledge funding from the Canadian Institutes of Health Research, the Rare Disease Models and Mechanisms Network (RDMM), and the Azrieli Foundation. Additionally, Shruti Kumar received support through a trainee fellowship from the RI-MUHC. The authors also thank the staff of the McGill Integrated Core of Animal Modeling (MICAM) and the Animal Resource Division of the RI-MUHC for their expert technical support.
About the publication
Shruti Kumar, Eric Barekea, Jimmy Leeb, Emma Carlsona, Fjodor Merkuric, Evelyn E. Schwagerc, Steven Maglioc, Jennifer L. Fishc, Jacek Majewskia, and Loydie A. Jerome-Majewska, Etiology of craniofacial and cardiac malformations in a mouse model of SF3B4-related syndromes. Proceedings of the National Academy of Sciences 121(39). September 18, 2024121 (39) e2405523121 https://doi.org/10.1073/pnas.2405523121
Related News
Loydie Jerome-Majewska receives the Anne McLaren Award
Researchers, advocates and patients gather on Rare Disease Research Day at the RI-MUHC