Defective cellular trafficking of missense NPR-B mutants is the major mechanism underlying acromesomelic dysplasia-type Maroteaux

Natriuretic peptides (NPs) comprise a family of structurallyrelated but genetically distinct hormones that regulate a varietyof physiological processes such as cardiac growth, blood pressure,axonal pathfinding and endochondral ossification leading tothe formation of vertebrae and long bones. The biological actionsof NPs are mediated by natriuretic peptide receptors (NPRs)A, B and C that are located on the cell surface. Mutations inNPR-B have been shown to cause acromesomelic dysplasia-typeMaroteaux (AMDM), a growth disorder in humans and severe dwarfismin mice. We hypothesized that missense mutations of NPR-B associatedwith AMDM primarily affect NPR-B function by the arrest of receptortrafficking at the endoplasmic reticulum (ER), due to conformationalchange, rather than an impairment of ligand binding, transmissionof signal through the membrane or catalytic activity. Twelvemissense mutations found in AMDM patients and cn/cn mice weregenerated by site-directed mutagenesis and transiently overexpressedin HeLa cells. Confocal microscopy revealed that 11 out of 12mutants were retained in the ER. Determination of the ligand-dependentcGMP response confirmed that ER-retained NPR-B mutants are non-functional.Meanwhile, the only cell surface-targeted NPR-B missense mutant(D176E) displayed greatly reduced enzymatic activity due toimpaired ligand binding. Thus, in the majority of cases of AMDMassociated with missense NPR-B mutation, disease appears toresult from defects in the targeting of the ER receptor to theplasma membrane.