RESUMO
OBJECTIVE: To define the genetic basis of a family with an autosomal, dominantly inherited form of spondyloepiphyseal dysplasia (SED) associated with tall stature. METHODS: A 6 generation family with early onset osteoarthritis (OA) associated with mild SED was studied. 14 individuals were examined clinically and radiologically, and DNA analysis was performed on 5. As the clinical pattern of joint involvement and tall stature of affected individuals resembled a family recently reported with an exon 11 mutation in COL2A1, this same mutation was specifically sought. In 2 clinically affected and 3 unaffected family members, exon 11 was amplified by polymerase chain reaction (PCR) followed by restriction 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 involvement of peripheral joints, in addition to spondylodysplasia, was seen in 14 members of the kindred. Affected family members had brachydactyly and were of average to above average height. Asp H1 digestion of the PCR product containing exon 11 in those with clinical disease was consistent with the presence of a mutation. Direct sequencing of this PCR product conclusively showed that a single base substitution was present in those with clinical disease, resulting in an arginine 75-cysteine (Arg75-Cys) mutation. CONCLUSION: We describe a 3rd family with an Arg75-Cys mutation with precocious generalized OA and mild SED. This finding supports the concept of mutational hot spots on COL2A1 related to the hypermutability of the cytosine-guanine doublet.