Trafficking defects and loss of ligand binding are the underlying causes of all reported DDR2 missense mutations found in SMED-SL patients

Abstract

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.

Consanguinity and Dysmorphology in Arabs

“…The Algerian family had a different mutation: c.2177T>G [1726R] [100] . In 2010, Ali et al [101] reported on the same mutation in a family from Egypt as originally reported by alGazali et al in 1996 [99] and on a novel mutation in a family from Pakistan who had a milder phenotype.…”

Squamous Cell Carcinoma of the Lung: Molecular Subtypes and Therapeutic Opportunities

“…Mutations may alter kinase activity, ligand binding, or DDR2 localization (28,29). In a study by Hammerman and colleagues (30), mutations were found in 11 of 290 SCC samples (3.8%).…”

Nrp1, a Neuronal Regulator, Enhances DDR2-ERK-Runx2 Cascade in Osteoblast Differentiation via Suppression of DDR2 Degradation

“…Loss of function of human or mouse Ddr2 gene leads to dysplasia in bones [20,21,22,23]. Therefore, the regulation of DDR2 in osteoblast differentiation is of great importance.…”

“…Ddr2 knockout mice and slie mice (mouse colony with spontaneous autosomal-recessive mutation in the Ddr2 locus) exhibit short long bones and irregular growth of flat bones [20]. Human Ddr2 gene mutation causes a rare form of dwarfism, spondylo-meta-epiphyseal dysplasia short limb-hand type (SMED-SL) [21,22,23]. Our and other's studies also demonstrated that DDR2 plays essential roles in osteoblast differentiation and chondrocyte maturation by modulating the phosphorylation and transactivity of Runx2 in an ERK MAPK-dependent manner [24,25].…”