Gene of the Month – March: EPHA2
Researchers from Germany and Japan identified EPHA2 as a new gene that causes Pendred syndrome if heterozygous mutations in the gene occur in combination with mutations in the SLC26A4 gene. Pendred syndrome is an autosomal recessively inherited disorder characterized by bilateral sensorineural hearing loss and enlargement of the thyroid gland (goitre), and, in most cases, an inner ear malformation called enlarged vestibular aqueduct (EVA). While in most patients biallelic mutations in SLC26A4 are detected as the underlying genetic cause, a number of patients carry monoallelic SLC26A4 mutations. SLC26A4 encodes pendrin, a protein which is predominantly expressed in epithelial cells of the inner ear, the thyroid gland and the kidney. It transports Cl-, I-, and HCO3 ions into and out of cells.
In their study, the researchers identified heterozygous mutations in EPHA2 in two patients with sensorineural hearing loss and EVA who also carried a heterozygous SLC26A4 mutation. Their functional animal and cell experiments revealed that the eph/ephrin system plays an unexpected role in pendrin regulation. Ephrins and their receptors, eph receptor tyrosine kinases, form a group of molecules that are essential in cell communication. The researchers demonstrated that pendrin interacts with EphA2 and that EphA2 mutations affect correct localization of pendrin in the mouse model. Furthermore, EphA2 appears to bind not only its classical binding partner ephrin-A1 but also ephrin-B2, which also results in interaction with pendrin, although this was weaker.
The results of the study have recently been published in Nature Communication.
Li M, Nishio SY, Naruse C, … Nakayama M. Digenic inheritance of mutations in EPHA2 and SLC26A4 in Pendred syndrome. Nat Commun Mar 12;11(1):1343. doi: 10.1038/s41467-020-15198-9.