Hope for Kids with Geleophysic Dysplasia
Article Summary
- A team of researchers led by Mustafa Tekin, M.D., developed the first viable animal model for the rare, genetic condition geleophysic dysplasia (GD).
- The researchers studied mutations in the ADAMTSL2 gene, which produces a protein that migrates from cells into the external network of molecules that supports tissues throughout the body.
- With the animal model established, Dr. Tekin and team now look to develop therapies to help treat GD.
An interdisciplinary team of researchers at the University of Miami Miller School of Medicine has developed the first viable animal model for geleophysic dysplasia (GD), a rare condition that affects tissues throughout the body.
The research team used the animal model and studied patients’ cells to comprehensively interrogate the genetic anomalies governing GD. The results were published in February 2024 in the journal JCI Insight. The long-term goal is to develop therapies for this severe condition.
“Children with this disease are usually small and have connective tissue problems affecting their skin, heart, bones, cartilage and lungs,” said Mustafa Tekin, M.D., professor and interim chair in the Dr. John T. Macdonald Foundation Department of Human Genetics at the Miller School and senior author on the paper. “Some die during childhood from heart and lung complications.”
This research was funded by the Al-Rashid Family Geleophysic Dysplasia Research Fund, which Ibrahim and Ryann Al-Rashid established in 2021 with a $3 million gift to the Miller School of Medicine. The Al-Rashid’s son has geleophysic dysplasia.
Targeting the ADAMTSL2 Gene
In the paper, the group studied a form of GD driven by mutations in the ADAMTSL2 gene. ADAMTSL2 produces a protein that migrates from cells into the external network of molecules that supports tissues throughout the body. Mutated proteins fail to launch and never reach the matrix to perform their vital functions.
The new model was given two ADAMTSL2 variations, p.R61H and p.A165T.
“We studied these two mutations and found p.A165T causes a more severe phenotype,” said Dr. Tekin. “It simply gets less of the protein to the extracellular matrix.”
Armed with this new research tool, the team conducted detailed experiments to better understand the disease. They found severe heart issues, including enlarged hearts. In some areas, connective tissues hardened to resemble cartilage. These findings closely match observed heart and lung issues in patients.
Moving Closer to Treatment
Only a fraction of the roughly 7,000 rare, genetic diseases that collectively affect more than 25 million people in the U.S. have viable treatments. Dr. Tekin has been investigating GD for several years, but the lack of an animal model slowed progress.
The animal model now allows Dr. Tekin’s team to explore new insights into the disease that might eventually lead to therapies. Perhaps the greatest benefit is that Dr. Tekin and colleagues can now test drugs to see if they can modify the disease.
“We’ve had some promising results in our efforts to understand the underlying mechanisms and develop potential interventions,” said Dr. Tekin. “We conducted drug screenings in the cells and identified several promising molecules. We are now testing some of those molecules in these models to see if they can help treat this difficult condition.”
Tags: Al-Rashid Family Geleophysic Dysplasia Research Fund, Dr. John T. Macdonald Foundation Department of Human Genetics, Dr. Mustafa Tekin, geleophysic dysplasia, genetics