title: A mutation in COL9A1 causes multiple epiphyseal dysplasia: further evidence for locus heterogeneity.
abstract: Multiple epiphyseal dysplasia (MED) is an autosomal dominantly inherited chondrodysplasia. It is clinically highly heterogeneous, partially because of its complex genetic background. Mutations in four genes, COL9A2, COL9A3, COMP, and MATR3, all coding for cartilage extracellular matrix components (i.e., the alpha2 and alpha 3 chains of collagen IX, cartilage oligomeric matrix protein, and matrilin-3), have been identified in this disease so far, but no mutations have yet been reported in the third collagen IX gene, COL9A1, which codes for the alpha1(IX) chain. MED with apparently recessive inheritance has been reported in some families. A homozygous R279W mutation was recently found in the diastrophic dysplasia sulfate transporter gene, DTDST, in a patient with MED who had a club foot and double-layered patella. The series consisted of 41 probands with MED, 16 of whom were familial and on 4 of whom linkage analyses were performed. Recombination was observed between COL9A1, COL9A2, COL9A3, and COMP and the MED phenotype in two of the families, and between COL9A2, COL9A3, and COMP and the phenotype in the other two families. Screening of COL9A1 for mutations in the two probands from the families in which this gene was not involved in the recombinations failed to identify any disease-causing mutations. The remaining 37 probands were screened for mutations in all three collagen IX genes and in the COMP gene. The probands with talipes deformities or multipartite patella were also screened for the R279W mutation in DTDST. The analysis resulted in identification of three mutations in COMP and one in COL9A1, but none in the other two collagen IX genes. Two of the probands with a multipartite patella had the homozygous DTDST mutation. The results show that mutations in COL9A1 can cause MED, but they also suggest that mutations in COL9A1, COL9A2, COL9A3, COMP, and DTDST are not the major causes of MED and that there exists at least one additional locus.
authors.affiliation: Collagen Research Unit, Biocenter and Department of Medical Biochemistry, University of Oulu, Oulu, Finland.
authors.forename: M
authors.initials: M
authors.lastname: Czarny-Ratajczak
authors.forename: J
authors.initials: J
authors.lastname: Lohiniva
authors.forename: P
authors.initials: P
authors.lastname: Rogala
authors.forename: K
authors.initials: K
authors.lastname: Kozlowski
authors.forename: M
authors.initials: M
authors.lastname: Perälä
authors.forename: L
authors.initials: L
authors.lastname: Carter
authors.forename: T D
authors.initials: TD
authors.lastname: Spector
authors.forename: L
authors.initials: L
authors.lastname: Kolodziej
authors.forename: U
authors.initials: U
authors.lastname: Seppänen
authors.forename: R
authors.initials: R
authors.lastname: Glazar
authors.forename: J
authors.initials: J
authors.lastname: Królewski
authors.forename: A
authors.initials: A
authors.lastname: Latos-Bielenska
authors.forename: L
authors.initials: L
authors.lastname: Ala-Kokko
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D027321:Anion Transport Proteins; D002352:Carrier Proteins / Q000235:genetics; D064236:Cartilage Oligomeric Matrix Protein; D002648:Child; D002675:Child, Preschool; D003094:Collagen / Q000235:genetics*; D024081:Collagen Type IX / Q000235:genetics*; D004252:DNA Mutational Analysis; D016326:Extracellular Matrix Proteins / Q000235:genetics; D005260:Female; D018740:Genetic Heterogeneity; D008040:Genetic Linkage / Q000235:genetics; D006023:Glycoproteins / Q000235:genetics; D006801:Humans; D007223:Infant; D008297:Male; D064235:Matrilin Proteins; D026901:Membrane Transport Proteins; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D010009:Osteochondrodysplasias / Q000000981:diagnostic imaging / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D011110:Polymorphism, Genetic / Q000235:genetics; 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; D003094:Collagen