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Nine Novel Growth Hormone Receptor Gene Mutations in Patients with Laron Syndrome¹

Laboratoire de Génétique Moléculaire, Institut National de la Santé et de la Recherche Médicale (INSERM) U91 (M-L.S., F.D., P.D., M.G., S.A.), Hôpital Henri Mondor, 94010 Créteil, France; and Hacettepe University, Division of Pediatric Endocrinology (N.K., N.Y.), Ankara, Turkey

Address all correspondence and requests for reprints to: Marie-Laure Sobrier, Laboratoire de Génétique Moléculaire, Institut National de la Santé et de la Recherche Médicale (INSERM) U91, Hôpital Henri Mondor, 51 Av. du Marechal de Lattre de Tassigny, 94010 Créteil, France.

The GH receptor (GHR) is a member of the cytokine receptor superfamily; GH binding protein is the solubilized extracellular domain of the GHR. Abnormalities in the GHR produce an autosomal recessive form of GH resistance, the Laron syndrome, characterized by growth failure and the clinical appearance of severe GH deficiency despite elevated circulating GH levels. In 13 unrelated patients with undetectable levels of GH binding protein, we characterized nine novel mutations in the GHR gene. These molecular defects comprise three nonsense mutations (Q65X, W80X, and W157X), one frameshift (36delC), two splice defects (GA at 70+1, CT at 723), and three missense mutations (C38S, S40L, and W50R) located in the extracellular domain of the receptor, and thus would be expected to interfere with GH binding activity. These results further confirm the broad heterogeneity of mutations underlying this rare GH resistance syndrome.