Genomewide scan for hand osteoarthritis: a novel mutation in matrilin-3.
Osteoarthritis (OA) is the most common human joint disease, characterized by loss and/or remodeling of joint synovium, cartilage, and bone. Here, we describe a genomewide linkage analysis of patients with idiopathic hand OA who were carefully phenotyped for involvement of either or both the distal interphalangeal (DIP) joints and the first carpometacarpal (CMC1) joints. The best linkage peaks were on chromosomes 4q and 3p and on the short arm of chromosome 2. Genomewide significance was reached for a locus on chromosome 2 for patients with affected CMC1 joints (LOD = 4.97); this locus was also significant for patients with OA in both CMC1 and DIP joints (LOD = 4.44). The peak LOD score at this locus coincides with a gene, MATN3, encoding the noncollagenous cartilage extracellular matrix protein, matrilin-3. Subsequent screening of the genomic sequence revealed a missense mutation, of a conserved amino acid codon, changing threonine to methionine in the epidermal growth factor-like domain in matrilin-3. The missense mutation cosegregates with hand OA in several families. The mutation frequency is slightly more than 2% in patients with hand OA in the Icelandic population and has a relative risk of 2.1.
Stefánsson
Stefán Einar
SE
deCode Genetics, Reykjavík, Iceland. stefan@decode.is
Jónsson
Helgi
H
Ingvarsson
Thorvaldur
T
Manolescu
Ileana
I
Jónsson
Hjörtur H
HH
Olafsdóttir
Gudbjörg
G
Pálsdóttir
Ebba
E
Stefánsdóttir
Gerdur
G
Sveinbjörnsdóttir
Gudfinna
G
Frigge
Michael L
ML
Kong
Augustine
A
Gulcher
Jeffrey R
JR
Stefánsson
Kári
K
D000595:Amino Acid Sequence; D002889:Chromosomes, Human, Pair 2; D002893:Chromosomes, Human, Pair 3; D002894:Chromosomes, Human, Pair 4; D015331:Cohort Studies; D016326:Extracellular Matrix Proteins / Q000235:genetics* / Q000378:metabolism; D005384:Finger Joint; D005787:Gene Frequency; D008040:Genetic Linkage; D005819:Genetic Markers; D005820:Genetic Testing / Q000379:methods*; D015894:Genome, Human; D006225:Hand; D006239:Haplotypes; D006801:Humans; D064235:Matrilin Proteins; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010003:Osteoarthritis / Q000175:diagnosis / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D011110:Polymorphism, Genetic; D017386:Sequence Homology, Amino Acid
D016326:Extracellular Matrix Proteins; D005819:Genetic Markers; D064235:Matrilin Proteins