FAT4 Gene Mutations Cause Many Abnormalities in the Lymphatic System

15:26, February 1, 2023

Defects in this gene cause everything in the body to swell - even the brain

Mutations in the FAT4 gene can cause Hennekam syndrome, which is characterized by various abnormalities of the lymphatic system. An international team of scientists from Russia (Ural Federal University), Afghanistan, Pakistan and China used molecular dynamic modeling to demonstrate the pathogenicity of the identified mutations. The data obtained will help to determine the predisposition to diseases associated with FAT4 gene activation. The study was supported by the Ministry of Science and Higher Education of the Russian Federation in the framework of the Priority 2030 program and published in the journal Informatics in Medicine Unlocked.

"Hennekam syndrome is a relatively rare (less than 1,000 cases have been reported worldwide) inherited disorder caused by mutations in three different genes - FAT4, ADAMTS3, CCBE1. Abnormalities in the lymphatic system cause everything in the body - including the brain - to swell. This is due to impaired lymphatic transport and, as a result, a large accumulation of protein-rich fluid in the intercellular space. As a result, any affected organ can increase in volume. Signs of this syndrome can also be developmental disorders, strange body deformities, a flat face with swollen eyelids," says Mikhail Bolkov, Senior Researcher at the Department of Immunochemistry at the Ural Federal University and the Institute of Immunology and Physiology, Ural Branch of the Russian Academy of Sciences.

The FAT4 gene is expressed in almost all tissues of the body. Newborns with Hennekam syndrome suffer from respiratory failure, which can have a variety of causes. In addition, a computed tomography scan may reveal various intra-abdominal abnormalities, and a magnetic resonance imaging scan will show the presence of brain lesions.

The scientists focused on studying mutations in the FAT4 gene: eleven predicted by the modeling study, three found in a particular patient, and five already known mutations. The results of the analysis showed that the identified mutations in the FAT4 gene indeed severely destabilize the structure and function of the protein. This information could lead to effective approaches for the diagnosis and treatment of this rare disease.

Currently, the main therapy for children or adults with Hennekam syndrome is the immunosuppressant sirolimus and other rapamycin-based drugs, says Mikhail Bolkov. Patients with Hennekam syndrome also need intravenous administration of albumin, because the body loses protein with edema, and prevention of complications of edema of the lungs, abdomen, and other organs. Most patients need a special diet, and in general the disease is difficult and requires special attention and constant monitoring by doctors.

In addition to bioinformatics studies, the researchers also studied the clinical characteristics of patients with Hennekam syndrome.

"The patient is already receiving ongoing therapy with a drug similar to rapamycin, which is commonly used in oncology. This drug is controlling the ascites and edema, but the disease has not regressed. Our main goal is to find new points of influence in the disease mechanism for possible drug therapy," says Mikhail Bolkov.

The scientists note that the results of the study will facilitate future genomic studies of Hennekam syndrome. Computer modeling can predict many aspects of the effects of mutations on proteins, leading to a cost-effective and rapid screening tool to guide diagnostic and experimental procedures. However, extensive clinical studies are needed to identify and refine important parameters and data, as well as experimental studies to validate the results. Scientists hope to be able to test the findings in practice in the future.

The news article was translated by UrFU International Marketing Office.
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