Mutations in DDR2 gene cause SMED with short limbs and abnormal calcifications

Am J Hum Genet. 2009 Jan;84(1):80-4. doi: 10.1016/j.ajhg.2008.12.004. Epub 2008 Dec 24.


The spondylo-meta-epiphyseal dysplasia [SMED] short limb-hand type [SMED-SL] is a rare autosomal-recessive disease, first reported by Borochowitz et al. in 1993.(1) Since then, 14 affected patients have been reported.(2-5) We diagnosed 6 patients from 5 different consanguineous Arab Muslim families from the Jerusalem area with SMED-SL. Additionally, we studied two patients from Algerian and Pakistani ancestry and the parents of the first Jewish patients reported.(1) Using a homozygosity mapping strategy, we located a candidate region on chromosome 1q23 spanning 2.4 Mb. The position of the Discoidin Domain Receptor 2 (DDR2) gene within the candidate region and the similarity of the ddr2 knockout mouse to the SMED patients' phenotype prompted us to study this gene(6). We identified three missense mutations c.2254 C > T [R752C], c. 2177 T > G [I726R], c.2138C > T [T713I] and one splice site mutation [IVS17+1g > a] in the conserved sequence encoding the tyrosine kinase domain of the DDR2 gene. The results of this study will permit an accurate early prenatal diagnosis and carrier screening for families at risk.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Calcinosis / enzymology
  • Calcinosis / genetics*
  • Chromosomes, Human, Pair 1 / genetics
  • Consanguinity
  • Discoidin Domain Receptors
  • Genetic Predisposition to Disease*
  • Hand Deformities, Congenital / enzymology
  • Hand Deformities, Congenital / genetics*
  • Humans
  • Molecular Sequence Data
  • Osteochondrodysplasias / enzymology
  • Osteochondrodysplasias / genetics*
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • Receptors, Mitogen / metabolism*
  • Young Adult


  • Receptors, Mitogen
  • Discoidin Domain Receptors
  • Receptor Protein-Tyrosine Kinases