Alternative titles; symbols
HGNC Approved Gene Symbol: DDR2
Cytogenetic location: 1q23.3 Genomic coordinates (GRCh38): 1:162,630,863-162,787,405 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q23.3 | Spondylometaepiphyseal dysplasia, short limb-hand type | 271665 | Autosomal recessive | 3 |
| Warburg-Cinotti syndrome | 618175 | Autosomal dominant | 3 |
Using a PCR-mediated approach, Karn et al. (1993) characterized cDNAs from human and mouse representing a novel type of receptor protein tyrosine kinase (RTK). The deduced 855-amino acid sequence of the longest ORF has a unique extracellular region encompassing a factor VIII-like domain, not previously described for RTKs. The most closely related RTKs are members of the neurotrophin receptors (TRKs; see TRKA, 191315), which show 47 to 49% homology with the kinase domain of the novel RTK. Therefore, Karn et al. (1993) called the novel gene TKT (pronounced 'ticket') for 'tyrosine-kinase related to TRK.' TKT orthologs from man and mouse are 98% similar. Northern blot analysis detected a 10-kb transcript that was highly expressed in heart and lung, with lower expression in brain, placenta, liver, skeletal muscle, and kidney. In mouse, highest expression was also detected in heart and lung, with lower expression in brain and testis.
Using in situ hybridization with 1-week-old mice, Labrador et al. (2001) found that Ddr2 was expressed along chondrocyte columns in the proliferative region of the growth plate. Ddr2 mRNA was also present, although dispersed, at areas of calcified cartilage in the cartilage-bone junction, as well as in the trabecular bone surface. Ddr2 protein was detected in most mouse tissues examined. Highest levels of phosphorylated Ddr2 were detected in lung, ovary, and skin, which did not correlate with Ddr2 protein levels.
By analysis of human/mouse somatic cell hybrids using PCR with primers that amplified human but not mouse genomic DNA, Karn et al. (1993) demonstrated that the TKT gene segregates with human chromosome 1 and is located in the region 1q12-qter.
Spondyloepiphyseal-Metaphyseal Dysplasia, Short Limb-Hand Type
Bargal et al. (2009) mapped the short limb-hand type of spondyloepiphyseal-metaphyseal dysplasia (SMED-SL; 271665) to a region on chromosome 1 that included that DDR2 gene. They considered DDR2 to be a strong candidate for the disorder because of the similarity between the phenotype of the Ddr2 knockout mouse and that of SMED-SL patients. In 8 patients from 7 different consanguineous families with SMED-SL, they identified homozygous missense mutations in exon 17 of the DDR2 gene: an R752C substitution (191311.0001) in 6 Arab Muslims living in the Jerusalem area, an I726R (191311.0002) substitution in 1 Algerian, and a T713I (191311.0003) substitution in 1 Pakistani. Bargal et al. (2009) also identified a splice site mutation (191311.0004) in the DDR2 gene, which resulted in the skipping of exon 17, in one of the Jewish families with SMED-SL originally reported by Borochowitz et al. (1993). All of the mutations occurred in the active site of the DDR2 tyrosine kinase domain.
Ali et al. (2010) reported homozygous DDR2 missense mutations in 2 consanguineous families with SMED-SL in the United Arab Emirates. One was a novel mutation (E113K; 191311.0005) in 2 sibs from a family of Pakistani origin, and the other the R752C mutation (191311.0001) in 2 Egyptian sibs. The authors expressed DDR2 constructs with the identified point mutations in human cell lines and evaluated their localization and functional properties. All SMED-SL missense mutants were defective in collagen-induced receptor activation, and the 3 missense mutations reported by Bargal et al. (2009) were retained in the endoplasmic reticulum. In contrast, the novel mutation trafficked normally but failed to bind collagen.
Warburg-Cinotti Syndrome
In 6 patients from 4 unrelated families with Warburg-Cinotti syndrome (WRCN; 618175), Xu et al. (2018) identified heterozygosity for missense mutations in the DDR2 gene (L610P, 191311.0006 and Y740C, 191311.0007). Functional analysis demonstrated that the mutations were activating, in contrast to the loss-of-function mutations that previously had been identified in patients with SMED-SL.
Labrador et al. (2001) obtained Ddr2 -/- mice at the expected mendelian ratio. Ddr2 -/- mice appeared normal at birth, but they failed to thrive, resulting in proportionate smaller body size and reduced body mass. They developed a progressive skeletal phenotype characterized by shortening of long bones, irregular growth of flat bones, and shorter snout. Reduced bone growth in Ddr2 -/- mice appeared to be due to reduced chondrocyte proliferation rather than apoptosis or a defect in chondrocyte differentiation. Ddr2 -/- embryonic fibroblasts and Ddr2 -/- adult skin fibroblasts proliferated more slowly and showed a diminished wounding response compared with wildtype fibroblasts.
In 6 patients with the short limb-hand type of spondylometaepiphyseal dysplasia (271665) from 5 Arab Muslim families living in the Jerusalem area, Bargal et al. (2009) identified homozygosity for a 2254C-T transition in exon 17 of the DDR2 gene, resulting in an arg752-to-cys (R752C) substitution. All of the parents were heterozygous for the mutation, which was not found in 200 chromosomes of matched healthy unrelated individuals. Haplotype analysis indicated that this is a founder mutation.
Ali et al. (2010) found that the 2 affected sibs from the consanguineous Egyptian family originally reported by Al-Gazali et al. (1996) carried the R752C mutation in homozygosity. Both sibs died, one of respiratory failure at age 13 years and the other of cord compression at age 8 years. In severity the phenotype was similar to the patients described by Bargal et al. (2009).
Ali et al. (2010) expressed R752C mutant protein in human cells and found that it was retained in endoplasmic reticulum and was defective in collagen-induced receptor activation.
In an Algerian patient with spondylometaepiphyseal dysplasia, short limb-hand type (271665), Bargal et al. (2009) identified homozygosity for a 2177T-G transversion in exon 17 of the DDR2 gene, resulting in an ile726-to-arg (I726R) substitution. The parents were heterozygous for the mutation, which was not found in 200 chromosomes of matched healthy unrelated individuals.
Ali et al. (2010) expressed I726R mutant protein in human cells and found that it was retained in endoplasmic reticulum and was defective in collagen-induced receptor activation.
In a Pakistani patient with spondylometaepiphyseal dysplasia, short limb-hand type (271665), Bargal et al. (2009) identified homozygosity for a 2138C-T transition in exon 17 of the DDR2 gene, resulting in a thr713-to-ile (T713I) substitution. The parents were heterozygous for the mutation, which was not found in 200 chromosomes of matched healthy unrelated individuals.
Ali et al. (2010) expressed T713I mutant protein in human cells and found that it was retained in endoplasmic reticulum and was defective in collagen-induced receptor activation.
In the parents of the affected members of one of the original consanguineous Jewish families with spondylometaepiphyseal dysplasia, short limb-hand type (271665), described by Borochowitz et al. (1993), Bargal et al. (2009) identified heterozygosity for an IVS17+1G-A mutation in the DDR2 gene, which resulted in the skipping of exon 17.
In 2 brothers from a consanguineous Pakistani family with spondylometaepiphyseal dysplasia, short limb-hand type (271665), Ali et al. (2010) detected homozygosity for a c.337G-A transition in DDR2 resulting in a glu-to-lys substitution at codon 113 (E113K). The E113K mutation is located in the extracellular discoidin domain and affects a surface-exposed residue important in the DDR2 collagen-binding site. The brothers had bowing of lower limbs in addition to short limbs and hands. Both had repeated respiratory infections. Neurologic development was normal in both.
Ali et al. (2010) expressed E113K mutant protein in human cells and found that, while it trafficked normally, it was defective in collagen-induced receptor activation and failed to bind collagen.
In a Danish man (patient 1) with Warburg-Cinotti syndrome (WRCN; 618175), who was originally reported by Warburg et al. (2006), and an unrelated 35-year-old woman with WCRN (patient 6), Xu et al. (2018) identified heterozygosity for a c.1829T-C transition (c.1829T-C, NM_001014796.1) in the DDR2 gene, resulting in a leu610-to-pro (L610P) substitution at a highly conserved residue within the tyrosine kinase domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was absent in the gnomAD database. DNA was not available from family members for segregation studies. Cultured fibroblasts from patient 1 showed more phosphorylated DDR2 than control fibroblasts, indicating that the L610P variant is activating and causes autophosphorylation of the receptor.
In an Italian man (patient 2) with Warburg-Cinotti syndrome (WRCN; 618175), who was originally reported by Cinotti et al. (2013), and a mother and 2 affected children (patients 3, 4, and 5), Xu et al. (2018) identified heterozygosity for a c.2219A-G transition (c.2219A-G, NM_001014796.1) in the DDR2 gene, resulting in a tyr740-to-cys (Y740C) substitution at a highly conserved residue within the tyrosine kinase domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was absent in the gnomAD database. It was shown to have arisen de novo in the mother and was not present in an unaffected daughter. Cultured fibroblasts from patient 3 showed more phosphorylated DDR2 than control fibroblasts, indicating that the Y740C variant is activating and causes autophosphorylation of the receptor.
Al-Gazali, L. I., Bakalinova, D., Sztriha, L. Spondylo-meta-epiphyseal dysplasia, short limb, abnormal calcification type. Clin. Dysmorph. 5: 197-206, 1996. [PubMed: 8818447]
Ali, B. R., Xu, H., Akawi, N. A., John, A., Karuvantevida, N. S., Langer, R., Al-Gazali, L., Leitinger, B. Trafficking defects and loss of ligand binding are the underlying causes of all reported DDR2 missense mutations found in SMED-SL patients. Hum. Molec. Genet. 19: 2239-2250, 2010. [PubMed: 20223752] [Full Text: https://doi.org/10.1093/hmg/ddq103]
Bargal, R., Cormier-Daire, V., Ben-Neriah, Z., Le Merrer, M., Sosna, J., Melki, J., Zangen, D. H., Smithson, S. F., Borochowitz, Z., Belostotsky, R., Raas-Rothschild, A. Mutations in DDR2 gene cause SMED with short limbs and abnormal calcifications. Am. J. Hum. Genet. 84: 80-84, 2009. [PubMed: 19110212] [Full Text: https://doi.org/10.1016/j.ajhg.2008.12.004]
Borochowitz, Z., Langer, L. O., Jr., Gruber, H. E., Lachman, R., Katznelson, M. B.-M., Rimoin, D. L. Spondylo-meta-epiphyseal dysplasia (SMED), short limb-hand type: a congenital familial skeletal dysplasia with distinctive features and histopathology. Am. J. Med. Genet. 45: 320-326, 1993. [PubMed: 8434618] [Full Text: https://doi.org/10.1002/ajmg.1320450308]
Cinotti, E., Ferrero, G., Paparo, F., Papadia, M., Faravelli, F., Rongioletti, F., Traverso, C., Di Maria, E. Arthropathy, osteolysis, keloids, relapsing conjunctival pannus and gingival overgrowth: a variant of polyfibromatosis? Am. J. Med. Genet. 161A: 1214-1220, 2013. [PubMed: 23637089] [Full Text: https://doi.org/10.1002/ajmg.a.35908]
Karn, T., Holtrich, U., Brauninger, A., Bohme, B., Wolf, G., Rubsamen-Waigmann, H., Strebhardt, K. Structure, expression and chromosomal mapping of TKT from man and mouse: a new subclass of receptor tyrosine kinases with a factor VIII-like domain. Oncogene 8: 3433-3440, 1993. [PubMed: 8247548]
Labrador, J. P., Azcoitia, V., Tuckermann, J., Lin, C., Olaso, E., Manes, S., Bruckner, K., Goergen, J.-L., Lemke, G., Yancopoulos, G., Angel, P., Martinez-A, C., Klein, R. The collagen receptor DDR2 regulates proliferation and its elimination leads to dwarfism. EMBO Rep. 2: 446-452, 2001. [PubMed: 11375938] [Full Text: https://doi.org/10.1093/embo-reports/kve094]
Warburg, M., Ullman, S., Jensen, H., Pedersen, H., Kobayashi, T., Russell, B., Tranebjaerg, L., Richard, G., Brondum-Nielsen, K. Blepharophimosis, corneal vascularization, deafness, and acroosteolysis: a 'new' syndrome? Am. J. Med. Genet. 140A: 2709-2713, 2006. [PubMed: 17103436] [Full Text: https://doi.org/10.1002/ajmg.a.31543]
Xu, L., Jensen, H., Johnston, J. J., Di Maria, E., Kloth, K., Cristea, I., Sapp, J. C., Darling, T. N., Huryn, L. A., Tranebjaerg, L., Cinotti, E., Kubisch, C., Rodahl, E., Bruland, O., Biesecker, L. G., Houge, G., Bredrup, C. Recurrent, activating variants in the receptor tyrosine kinase DDR2 cause Warburg-Cinotti syndrome. Am. J. Hum. Genet. 103: 976-983, 2018. [PubMed: 30449416] [Full Text: https://doi.org/10.1016/j.ajhg.2018.10.013]