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Primary Growth Hormone (GH) Insensitivity and Insulin-Like Growth Factor Deficiency Caused by Novel Compound Heterozygous Mutations of the GH Receptor Gene: Genetic and Functional Studies of Simple and Compound Heterozygous States

Department of Pediatrics (P.F., B.M.L., K.L.P., V.H., R.G.R.), Oregon Health and Science University, Portland, Oregon 97239-3098; Department of Pediatrics (S.R., G.H., H.F.), University of Vienna, 1090 Vienna, Austria; Institut National de la Santé et de la Recherche Médicale U654 (S.A.), Hopital Henri Mondor, 94010 Creteil Cedex, France; St. Anna Children’s Hospital (H.F.), A-1090 Vienna, Austria; Lucile Packard Foundation for Children’s Health (R.G.R.), Palo Alto, California 94304; and Department of Pediatrics (R.G.R.), Stanford University, Stanford, California 94305-2038

Address all correspondence and requests for reprints to: Dr. Stefan Riedl, Department of Pediatrics, University of Vienna, 1090 Vienna, Austria. E-mail: stefan.riedl{at}meduniwien.ac.at; or Dr. Vivian Hwa, Department of Pediatrics, NRC5, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 9723-3098. E-mail: hwav{at}ohsu.edu.

Context: Primary GH insensitivity (GHI) or Laron syndrome, caused by mutations of the GH receptor (GHR) gene, has a clinical phenotype of postnatal growth failure associated with normal elevated serum concentrations of GH and low serum levels of IGF-I.

Objective: We investigated the clinical and biochemical implications of molecular defects in the GHR gene in an Austrian family with two daughters who were GHI.

Patients: Patient 1 [height, –4.8 SD score (SDS)] and patient 2 (height, –5.0 SDS) had elevated circulating levels of GH, low-normal levels of GH-binding protein, and abnormally low IGF-I (–5.0 SDS and –2.6 SDS, respectively) and IGF-binding protein-3 (–2.6 SDS and –2.0 SDS, respectively).

Results: Both patients carry novel compound, missense, heterozygous GHR mutations, C94S and H150Q. In vitro reconstitution experiments demonstrated that whereas each of the mutants could be stably expressed, GHR(C94S) lost its affinity for GH and could neither activate signal transducer and activator of transcription (STAT)-5b nor drive STAT5b-dependent gene transcription in response to GH (1–100 ng/ml). GHR(H150Q) showed normal affinity for GH but impaired capacity for signal transduction. The compound heterozygote and C94S heterozygote, but not the H150Q heterozygote, showed significant deficiency in activating GH-induced gene expression, corroborating diminished GH-induced STAT5b activation in fibroblasts carrying GHR(C94S) as either a compound heterozygote (in the patients) or a simple heterozygote (in one parent).

Conclusions: Each of the compound heterozygous mutations contributed additively to the pathological condition seen in the patients, and the more detrimental of the two mutations, C94S, may cause (partial) primary GHI, even in a heterozygous state.

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				P. Fang, R. Girgis, B. M. Little, K. L. Pratt, J. Guevara-Aguirre, V. Hwa, and R. G. Rosenfeld Growth Hormone (GH) Insensitivity and Insulin-Like Growth Factor-I Deficiency in Inuit Subjects and an Ecuadorian Cohort: Functional Studies of Two Codon 180 GH Receptor Gene Mutations J. Clin. Endocrinol. Metab., March 1, 2008; 93(3): 1030 - 1037. [Abstract] [Full Text] [PDF]