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Spondylo-meta-epiphyseal dysplasia (SMED) with short limbs and abnormal calcifications (SMED-SL) is a rare, autosomal recessive human growth disorder, characterized by disproportionate short stature, short limbs, short broad fingers, abnormal metaphyses and epiphyses, platyspondyly and premature calcifications. Recently, three missense mutations and one splice-site mutation in the DDR2 gene were identified as causative genetic defects for SMED-SL, but the underlying cellular and biochemical mechanisms were not explored. Here we report a novel DDR2 missense mutation, c.337G>A (p.E113K), that causes SMED-SL in two siblings in the United Arab Emirates. Another DDR2 missense mutation, c.2254C>T (p.R752C), matching one of the previously reported SMED-SL mutations, was found in a second affected family. DDR2 is a plasma membrane receptor tyrosine kinase that functions as a collagen receptor. We expressed DDR2 constructs with the identified point mutations in human cell lines and evaluated their localization and functional properties. We found that all SMED-SL missense mutants were defective in collagen-induced receptor activation and that the three previously reported mutants (p.T713I, p.I726R and p.R752C) were retained in the endoplasmic reticulum. The novel mutant (p.E113K), in contrast, trafficked normally, like wild-type DDR2, but failed to bind collagen. This finding is in agreement with our recent structural data identifying Glu113 as an important amino acid in the DDR2 ligand-binding site. Our data thus demonstrate that SMED-SL can result from at least two different loss-of-function mechanisms: namely defects in DDR2 targeting to the plasma membrane or the loss of its ligand-binding activity.

Original publication

DOI

10.1093/hmg/ddq103

Type

Journal article

Journal

Hum Mol Genet

Publication Date

01/06/2010

Volume

19

Pages

2239 - 2250

Keywords

Base Sequence, Child, DNA Primers, Discoidin Domain Receptors, Endoplasmic Reticulum, HeLa Cells, Humans, Immunohistochemistry, Male, Models, Molecular, Molecular Sequence Data, Mutation, Missense, Osteochondrodysplasias, Pedigree, Protein Binding, Protein Transport, Radiography, Receptor Protein-Tyrosine Kinases, Receptors, Collagen, Receptors, Mitogen, Sequence Analysis, DNA, Signal Transduction, Transfection, United Arab Emirates