JANSEN-TYPE METAPHYSEAL CHONDRODYSPLASIA - ANALYSIS OF PTH PTH-RELATED PROTEIN-RECEPTOR MESSENGER-RNA BY THE REVERSE-TRANSCRIPTASE POLYMERASE CHAIN METHOD/

Jansen-type metaphyseal chondrodysplasia (JMC) has both delayed ossifi cation in long bones and usually hypercalcemia. We report a Japanese m ale patient with JMC who presented with rachitic signs on radiographs, hypercalcemia (13 mg/dl) and low %TRP at age 3 months (mo). Hypercalc emia was treated from age 3 mo to 11 yr. Progressive widening, splayin g and fragmentation of the metaphyses have been recognized on radiogra phs which resulted in shortened tubular bones and consequent short sta ture [107 cm (-6.5 SD)] at age 13 yr. Hypercalcemia tended to normaliz e, and %TRP became normal at age 13 yr. Repeated measurements of serum PTH and PTH-related protein (PTHrP) levels showed that they were low or normal in the face of hypercalcemia and high urine cAMP excretion, which led us to suspect constitutive activation of the PTH/PTHrP recep tor. Direct sequencing of PTH/PTHrP receptor complementary DNA from sk in fibroblast cells revealed a CAC to CGC transversion yielding a stri ctly conserved His(223) to Arg substitution found in 90% of DNA fragme nt in the second transmembrane domain of the receptor. This mutation c reated a restriction site SphI (G/CATG/C). Direct sequencing of genomi c DNA and also restriction enzyme digestion revealed heterozygous tran sition. The mutation was absent in the parents with normal phenotype. We conclude that both dysplastic bone lesions and calcium homeostasis are age-dependent in JMC, and that the His(223)-Arg substitution is th e same as that found in four Caucasian patients with a similar phenoty pe irrespective of the ethnic difference, and that the preferential ex pression of an abnormal allele of the PTH/PTHrP receptor mRNA in skin fibroblast despite heterogygotic transversion in the genomic DNA sugge sts the importance of allele expression.