Autosomal dominant late-onset retinal macular degeneration (L-ORMD) is caused by a single S163R mutation in the C1q and tumor necrosis factor-related protein 5 (C1QTNF5) gene. The C1QTNF5 gene encodes a secreted and membrane-associated protein involved in adhesion of retinal pigmented epithelial cells (RPE) to Bruch's membrane. The crystal structure of the trimeric globular domain of human C1QTNF5 at 1.34 angstrom resolution reveals unique features of this novel C1q family member. It lacks a Ca2+-binding site, displays a remarkable non-uniform distribution of surface electrostatic potentials and possesses a unique sequence (F(181)F(182)G(183)G(184)W(185)P(186)) that forms a hydrophobic plateau surrounded by Lys and Arg residues with a solvent cavity underneath. S-163 forms a hydrogen bond with F-182 in a hydrophobic area extending to the hydrophobic plateau. The pathogenic mutation S163R disrupts this hydrogen bonding and positively charges these hydrophobic areas. Thus, our analysis provides insights into the structural basis of the L-ORMD disease mechanism. (C) 2012 Elsevier Inc. All rights reserved.