Professor André Mégarbané with Doctors Éliane Choueiry and Cybel Mehawej. (Courtesy of LAU)
The team from the Department of Human Genetics at the Gilbert and Rose-Marie Chagoury School of Medicine at the Lebanese American University (LAU) has identified a rare genetic disease linked to the SH3GL1 gene, which is concerned mostly with endocytosis and intracellular signaling pathways.
The condition corresponds to a form of primary immunodeficiency caused by a lack of the endophilin A2 protein, which this gene encodes. The deficiency of A2 affects the production of antibodies, weakening a person's natural defenses.
The study was published in November in the Journal of Clinical Immunology and led by Professor André Mégarbané, associate dean for research and director of the aforementioned department along with Dr. Cybel Mehawej and Dr. Éliane Choueiry, associate professors at the Chagoury School of Medicine.
The research was co-funded by the President's Intramural Research Fund (PIRF) and the L'Oréal-Unesco Young Talents for Women in Science fellowship, with the aim of deepening the science community's understanding of the endophilin A2 protein and its role in the body's immune response.
Mehawej hopes her team's findings will lead to "the development of new therapies" and allow clinicians to diagnose the deficiency more accurately, intervene earlier, and improve patient care to avoid complications related to the disease.
Identifying the genetic cause of the yet-unnamed disease, she says, would mean patients could receive better informed treatment and gain a deeper understanding of their health. In Lebanon, it is estimated that around 200,000 people suffer from rare diseases, often due to close relatives having children.
The team of researchers was initially drawn to the topic when a 14-year-old patient suspected of having a rare and unknown immunodeficiency disease was referred to the department by his physician, Dr. Roula Farah. "The patient exhibited symptoms suggesting an abnormal immune response, but standard genetic tests had not provided conclusive results as the genetic cause of his condition had not yet been identified," says Mehawej.
"We did not detect what we call mutations, alterations, or genetic variations in genes known to be involved in immune deficiencies. That’s when we thought there must be a new genetic cause because the patient suffered from recurrent infections and had been receiving what are called intravenous immunoglobulins or IVIg since the age of six, as his body is unable to produce them," she recalls.
"We then conducted more research and studied all the genes using high-throughput sequencing techniques, which allowed us to identify a candidate alteration in the SH3GL1 gene," she explains. "Through slightly more sophisticated tests on blood samples from the patient, we subsequently confirmed that what we observed at the DNA level and suspected to be potentially the cause of his disease is indeed what caused his disease, and thus we discovered this genetic disease which is a new form of humoral immune deficiency, meaning it specifically affects antibody production."
Advancing human genetics
LAU's human genetics research department is involved in several ambitious projects. The team recently conducted an innovative study on the POLD3 gene, a key player in DNA replication and repair, which its researchers had associated in 2013 with a syndrome of immunodeficiency and congenital deafness.
Published in the October issue of the European Journal of Human Genetics, the study is the first to establish a link between heterozygous variants (alterations affecting one of the two copies of a gene, each inherited from a parent) of the POLD3 gene and the progressive decline of hearing and balance disorders in individuals over 40 years old.
"This opens up opportunities for us to establish more collaborations," Mehawej says. She sees cooperation and knowledge sharing among scientific communities locally and abroad as crucial to efficiency and development. "We are fortunate to be at LAU," she says, "which places great value on research and invests a lot to contribute to scientific knowledge. The university is making efforts in all areas to encourage the entire academic community to conduct research work."
LAU's Department of Human Genetics' pursuits are focused on research in the field of human genetics, particularly in the areas of deafness, primary immune deficiencies, and genetic and neurological malformations. But beyond what its researchers do in the lab, the department is also working to promote genetic education for future doctors and the community by raising awareness of genetic disorders and consanguinity through seminars and activities. It also provides services and tests at reduced prices to patients and their families, including clinical and molecular diagnosis in addition to genetic counseling.
"We perform some analyses in-house and maintain data confidentially for life if the patient needs to undergo tests again," Mehawej says. "We reanalyze for free without additional charge. Our goal is to serve patients, the community, genetics, and research."
