Simpson-Golabi-Behmel Syndrome Associated With a Missense Variant at the Signal Peptide Cleavage Site of GPC3

Translocation of newly synthesized proteins into the lumen of the endoplasmic reticulum (ER) is mediated by signal peptide recognition and cleavage. Here we report an individual with Simpson-Golabi-Behmel syndrome (SGBS) bearing a GPC3 missense variant at the signal peptide cleavage site of the glypican-3 protein. The c.71C>T; p.(Ala24Val) alteration in the key -1 position of the cleavage greatly reduces cleavage of the signal peptide, resulting in failure of the protein to efficiently exit the ER, and impaired glycosylation. Functional characterization of two other engineered variants at this position-one predicted to permit cleavage and the other to prevent it-corroborates our findings. This case highlights the potential for missense variants within the signal peptide cleavage site to underlie genetic disorders, and reinforces the idea that many of the missense variants in GPC3 that cause SGBS reside in motifs with high functional relevance to the processing and maturation of glypican-3.