Lack of the human choline transporter-like protein CTL2 causes hearing impairment and a rare red blood cell phenotype

Recent genome-wide association and murine studies identified the human neutrophil antigen -3a/b polymorphism (HNA-3a/b) in SLC44A2 (rs2288904-G/A) as a risk factor in venous thromboembolism (VTE). The choline transporter-like protein CTL2 encoded by the SLC44A2 gene plays an important role in platelet aggregation and neutrophil interaction with the von Willebrand factor. By investigating alloantibodies to a high-prevalence antigen of unknown specificity, found in patients with a rare blood type, we showed that CTL2 is also expressed in red blood cells and carries a new blood group system. Furthermore, we identified three siblings of European ancestry who are homozygous for a large deletion in SLC44A2, resulting in complete CTL2 deficiency. Interestingly, the first-ever reported CTL2-deficient individuals suffer from progressive hearing impairment, recurrent arterial aneurysms and epilepsy. In contrast to Slc44a2-/- mice, CTL2null individuals showed normal platelet aggregation and do not suffer from any apparent hematological disorders. In addition, CD34+ cells from CTL2null patients undergo normal ex vivo erythropoiesis, indicating that CTL2 is not essential for erythroid proliferation and differentiation. Overall, our findings confirm the function of CTL2 in hearing preservation and provide new insights into the possible role of this protein in maintaining cerebrovascular homeostasis.