Truncation of TGF-beta docking receptor GARP is linked to human disease

摘要

Transforming growth factor-P (TGF-P) is a pleotropic cytokine that plays important roles in development, immune tolerance, cancer and a myriad of other processes. It is made as a latent form which requires subsequent binding to TGF-P milieu molecules for activation in a highly tempo-spatially regulated fashion to carry out its function [1]. Two cell surface TGF-P milieu molecules have been described, including Leucine Rich Repeat Containing Protein 32 (LRRC32) [2] and LRRC33 [1]. Glycoprotein-A Repetitions Predominant (GARP), encoded by LRRC32, is a type I transmembrane protein with a large extracellular domain for cell surface docking and activation of all three isoforms of latent TGF-p: TGF-pl, TGF-p2 and TGF-P3. GARP has gained increasing attention due to its important roles in immune tolerance [3] and palatogenesis [4] from mouse genetic studies. Genome-wide association study and targeted next-generation sequencing of 11q13.5 in humans has previously linked missense mutation of GARP to atopic dermatitis [5]. In this issue of EJHG, Harel et al. [6] reported three human cases of developmental delay, cleft palate and proliferative retinopathy with homozygous point mutation of LRRC32. The mutation leads to premature termination of GARP translation (GARP~(Arg544Ter)) and presumably a production of soluble GARP without the transmembrane domain. The biochemical confirmation of soluble GARP~(Arg544Ter) was not provided.