LOSS-OF-FUNCTION MUTATIONS IN CARBOXYPEPTIDASE D CAUSE A NEW SYNDROME WITH LYMPHEDEMA AND SENSORINEURAL HEARING LOSS

Abstract

Lymphedema is the consequence of inefficient uptake and/or reduced lymph flow, which leads to the accumulation of high-protein fluid beneath the skin and chronic swelling of extremities. Here, we report three individuals diagnosed with a new recessive syndrome presenting with progressive lymphedema and sensorineural hearing loss (SNHL). Whole-exome sequencing identified causative mutations, including a protein-null allele, in CPD which encodes for Carboxypeptidase D. We successfully established cpda knock-out zebrafish lines, which revealed severe developmental defects in the lymphatic system. Resulting in the development of lymphedema, successfully modelling the patient phenotype. CPD is a circulating protease which hydrolyses proteins with a lysine or arginine at their C-terminus. To date, no endogenous substrates for CPD have been identified. Using patient-derived primary cells and our zebrafish knockout animals, we aim to understand the pathogenesis of this new disease to develop CPD as a potential therapeutic for the treatment of lymphedema.