HEREDITARY OSTEOARTHRITIS WITH MILD SPONDYLOEPIPHYSEAL DYSPLASIA - ARE THERE HOT-SPOTS ON COL2A1

Objective. To define the genetic basis of a family with an autosomal, dominantly inherited form of spondyloepiphyseal dysplasia (SED) associ ated with tall stature, Methods. A 6 generation family with early onse t osteoarthritis (OA) associated with mild SED was studied. 14 individ uals were examined clinically and radiologically, and DNA analysis was performed on 5, As the clinical pattern of joint involvement and tail stature of affected individuals resembled a family recently reported with an exon Ii mutation in COL2A1, this same mutation was specificall y sought, In 2 clinically affected and 3 unaffected family members, ex on II was amplified by polymerase chain reaction (PCR) followed by res triction enzyme digestion with Asp H1, the enzyme recognition sequence of which is altered by the mutation. The PCR product containing exon 11 was then directly sequenced. Results, OA with widespread involvemen t of peripheral joints, in addition to spondylodysplasia, was seen in 14 members of the kindred. Affected family members had brachydactyly a nd were of average to above average height. Asp ill digestion of the P CR product containing exon 11 in those with clinical disease was consi stent with the presence of a mutation, Direct sequencing of this PCR p roduct conclusively showed that a single base substitution was present in those with clinical disease, resulting in an arginine(75)-cysteine (Arg(75)-Cys) mutation. Conclusion. We describe a 3rd family with an Arg(75)-Cys mutation with precocious generalized OA and mild SED, This finding supports the concept of mutational hut spots on COL2A1 relate d to the hypermutability of the cytosine-guanine doublet.