title: Mutations in the known genes are not the major cause of MED; distinctive phenotypic entities among patients with no identified mutations.
abstract: Multiple epiphyseal dysplasia (MED) is a clinically and genetically heterogeneous chondrodysplasia. Mutations in six genes (COMP, COL9A1, COL9A2, COL9A3, MATN3 and DTDST) have been reported, but the genotype-phenotype correlations and the proportions of cases due to mutations in these genes are still not well characterized. We performed a clinical, radiological and molecular analysis of known MED genes on 29 consecutive MED patients. The mutation analysis resulted in identification of the DTDST mutation in four patients (14%), the COMP mutation in three (10%) and the MATN3 mutation in three (10%). Thus, a disease-causing mutation was identified in 10 patients altogether (34%). The phenotypic features observed in the patients with mutations were in accordance with previously described phenotypes, but two new distinct phenotypic entities were identified in patients in whom no mutation was found. One of them was characterized by severe, early-onset dysplasia of the proximal femurs with almost complete absence of the secondary ossification centres and abnormal development of the femoral necks. The other phenotype was characterized by 'mini-epiphyses', resulting in severe dysplasia of the proximal femoral heads. The findings suggest that mutations in the known genes are not the major cause of MED and are responsible for less than half of the cases. The existence of additional MED loci is supported by the exclusion of known loci by mutation analysis and finding of specific subgroups among these patients.
authors.affiliation: Collagen Research Unit, Biocenter and Department of Medical Biochemistry and Molecular Biology, University of Oulu, Oulu, Finland.
authors.forename: Eveliina
authors.initials: E
authors.lastname: Jakkula
authors.forename: Outi
authors.initials: O
authors.lastname: Mäkitie
authors.forename: Malwina
authors.initials: M
authors.lastname: Czarny-Ratajczak
authors.forename: Malwina
authors.initials: M
authors.lastname: Czarny-Ratacjzak
authors.forename: Gail C
authors.initials: GC
authors.lastname: Jackson
authors.forename: Rita
authors.initials: R
authors.lastname: Damignani
authors.forename: Miki
authors.initials: M
authors.lastname: Susic
authors.forename: Michael D
authors.initials: MD
authors.lastname: Briggs
authors.forename: William G
authors.initials: WG
authors.lastname: Cole
authors.forename: Leena
authors.initials: L
authors.lastname: Ala-Kokko
mesh_terms: D000293:Adolescent; D000328:Adult; D027321:Anion Transport Proteins; D002352:Carrier Proteins / Q000235:genetics; D064236:Cartilage Oligomeric Matrix Protein; D002648:Child; D002675:Child, Preschool; D024081:Collagen Type IX / Q000235:genetics; D004252:DNA Mutational Analysis; D016326:Extracellular Matrix Proteins / Q000235:genetics; D005260:Female; D006023:Glycoproteins / Q000235:genetics; D006801:Humans; D008297:Male; D064235:Matrilin Proteins; D026901:Membrane Transport Proteins; D009154:Mutation; D010009:Osteochondrodysplasias / Q000000981:diagnostic imaging / Q000235:genetics*; D010641:Phenotype; D012313:RNA / Q000032:analysis; D011859:Radiography; D000076988:Sulfate Transporters
chemical_list: D027321:Anion Transport Proteins; C439970:COL9A1 protein, human; C120282:COL9A2 protein, human; C120768:COL9A3 protein, human; D002352:Carrier Proteins; D064236:Cartilage Oligomeric Matrix Protein; D024081:Collagen Type IX; D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; D064235:Matrilin Proteins; D026901:Membrane Transport Proteins; C089651:SLC26A2 protein, human; D000076988:Sulfate Transporters; C577553:TSP5 protein, human; D012313:RNA