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

Abstract

Natriuretic peptides (NPs) comprise a family of structurally related but genetically distinct hormones that regulate a variety of physiological processes such as cardiac growth, blood pressure, axonal pathfinding and endochondral ossification leading to the formation of vertebrae and long bones. The biological actions of NPs are mediated by natriuretic peptide receptors (NPRs) A, B and C that are located on the cell surface. Mutations in NPR-B have been shown to cause acromesomelic dysplasia-type Maroteaux (AMDM), a growth disorder in humans and severe dwarfism in mice. We hypothesized that missense mutations of NPR-B associated with AMDM primarily affect NPR-B function by the arrest of receptor trafficking at the endoplasmic reticulum (ER), due to conformational change, rather than an impairment of ligand binding, transmission of signal through the membrane or catalytic activity. Twelve missense mutations found in AMDM patients and cn/cn mice were generated by site-directed mutagenesis and transiently overexpressed in HeLa cells. Confocal microscopy revealed that 11 out of 12 mutants were retained in the ER. Determination of the ligand-dependent cGMP 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 to impaired ligand binding. Thus, in the majority of cases of AMDM associated with missense NPR-B mutation, disease appears to result from defects in the targeting of the ER receptor to the plasma membrane.

• Authors: Alistair N Hume, Jens Buttgereit, Aydah M Al-Awadhi, Sarah S Al-Suwaidi, Anne John, Michael Bader, Miguel C Seabra, Lihadh Al-Gazali, Bassam R Ali
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 18 Issue 2 Pg. 267-77 (Jan 15 2009) ISSN: 1460-2083 [Electronic] England
• PMID: 18945719 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Receptors, Atrial Natriuretic Factor
• atrial natriuretic factor receptor B

Topics

• Cell Membrane (genetics, metabolism)
• Endoplasmic Reticulum (genetics, metabolism)
• HeLa Cells
• Humans
• Mucopolysaccharidosis VI (genetics, metabolism)
• Mutation, Missense
• Protein Transport
• Receptors, Atrial Natriuretic Factor (genetics, metabolism)