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

Abstract

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.

Figure 1

Clinical Picture and Roentgen of the Hands (A and B) Picture of the hands of 2 patients with typical broad, puffy fingers and short, broad nails. (C) Hand radiography of patient A shows irregular widened distal radius and ulna. The metacarpals are short and have a narrow neck with meta-epiphyseal widening and distal pointing.

Figure 2

Roentgen of the Cervical Spine, Chest, and Computerized Tomography of the Head and Chest of a 16-Year-Old Patient Lateral cervical radiography (A) and chest CT (B) showing heavily calcified larynx and tracheal rings (white arrows). (C) Brain CT of the 16-year-old patient demonstrates choroid plexus calcifications not seen normally at this age (white arrow). (D) Chest radiography demonstrates widened ribs and a heavily calcified distal bronchial tree (white arrow).

Figure 3

Antero-Posterior Radiography of the Pelvis, Femurs, and Knees of the 16-Year-Old Patient Dense calcifications are projected over the left femoral head pubis and ischium (two arrows). The right acetabulum is flattened and irregular and shows a varus deformity of the femoral neck. The femurs and tibia metaphyses are widened.

Figure 4

Partial Pedigrees of the Five Arab Muslim Jerusalem Families and Haplotype Analysis Using Three Microsatellite Markers, D1S2675, D1S2768, and D1S2844, in the Critical Region on Chromosome 1q23, Showing a Common Haplotype The microsatellite markers are shown in the upper left panel. An asterisk indicates the three patients studied by SNP analysis.

Figure 5

RT-PCR of the DDR2 c.DNA and Partial Alignment of the Human DDR2 Tyrosine Kinase Domain with Sequences from Four Different Species (A) RT-PCR of the DDR2 c.DNA (fragment E). Panel 1: Heterozygous parent for IVS17+1g > a (Lymphoblastoid line). Panels 2 and 3: Normal control (lymphoblastoid line and fibroblasts, respectively). Sequencing of band c showed skipping of exon 17, band b showed partial skipping of exon 17, and band a represents the normal allele. (B) Partial alignment of the human DDR2 tyrosine kinase domain with sequences from four different species. The mutated residues T713C, I726R, and R752C, highlighted and indicated by arrows, are found in SMED patients and are localized in the active site of the DDR2 tyrosine kinase domain.