Jf. Bleasel et al., HEREDITARY OSTEOARTHRITIS WITH MILD SPONDYLOEPIPHYSEAL DYSPLASIA - ARE THERE HOT-SPOTS ON COL2A1, Journal of rheumatology, 23(9), 1996, pp. 1594-1598
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.