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

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Item Type:	Article
Title:	Defective cellular trafficking of missense NPR-B mutants is the major mechanism underlying Acromesomelic Dysplasia type Maroteaux
Creators Name:	Hume, A.N., Buttgereit, J., Al-Awadhi, A.M., Al-Suwaidi, S.S., John, A., Bader, M., Seabra, M.C., Al-Gazali, L. and Ali, B.R.
Abstract:	The 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 path-finding and endochondral ossification leading to the formation of vertebrae and long bones. The biological actions of NP 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 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 over-expressed 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 targeting of the ER receptor to the plasma membrane.
Keywords:	Cell Membrane, Endoplasmic Reticulum, Hela Cells, Mucopolysaccharidosis VI, Missense Mutation, Protein Transport, Atrial Natriuretic Factor Receptors
Source:	Human Molecular Genetics
ISSN:	0964-6906
Publisher:	Oxford University Press
Volume:	18
Number:	2
Page Range:	267-277
Date:	15 January 2009
Official Publication:	https://doi.org/10.1093/hmg/ddn354
PubMed:	View item in PubMed

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