Mutations in DDR2 gene cause SMED with short limbs and abnormal calcifications.
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.
Bargal
Ruth
R
Department of Human Genetics, Hadassah Hebrew University Hospital, POB 12000, Jerusalem, 91120, Israel.
Cormier-Daire
Valerie
V
Ben-Neriah
Ziva
Z
Le Merrer
Martine
M
Sosna
Jacob
J
Melki
Judith
J
Zangen
David H
DH
Smithson
Sarah F
SF
Borochowitz
Zvi
Z
Belostotsky
Ruth
R
Raas-Rothschild
Annick
A
D000595:Amino Acid Sequence; D002114:Calcinosis / Q000201:enzymology / Q000235:genetics*; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D003241:Consanguinity; D000070818:Discoidin Domain Receptors; D020022:Genetic Predisposition to Disease; D006228:Hand Deformities, Congenital / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D010009:Osteochondrodysplasias / Q000201:enzymology / Q000235:genetics*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D011975:Receptors, Mitogen / Q000378:metabolism*; D055815:Young Adult
D011975:Receptors, Mitogen; D000070818:Discoidin Domain Receptors; D020794:Receptor Protein-Tyrosine Kinases