9 NOVEL GROWTH-HORMONE RECEPTOR GENE-MUTATIONS IN PATIENTS WITH LARONSYNDROME

The GH receptor (GHR) is a member of the cytokine receptor superfamily ; GH binding protein is the solubilized extracellular domain of the GH R. Abnormalities in the GHR produce an autosomal recessive form of GH resistance, the Laron syndrome, characterized by growth failure and th e clinical appearance of severe GH deficiency despite elevated circula ting GH levels. In 13 unrelated patients with undetectable levels of G H binding protein, we characterized nine novel mutations in the GHR ge ne. These molecular defects comprise three nonsense mutations (Q65X, W 80X, and W157X), one frameshift (36delC), two splice defects (G-->A at 70+1, C-->T at 723), and three missense mutations (C38S, S40L, and W5 0R) located in the extracellular domain of the receptor, and thus woul d be expected to interfere with GH binding activity. These results fur ther confirm the broad heterogeneity of mutations underlying this rare GH resistance syndrome.