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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

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 (R.G.), University of Alberta, Edmonton, Canada AB T6G2B7; the Institute of Endocrinology, Metabolism, and Reproduction (J. G.-A.), Quito, Ecuador; Lucile Packard Foundation for Children’s Health (R.G.R.), Palo Alto, California 94304; and Department of Pediatrics, Stanford University (R.G.R), Stanford, California 94305-2038

Address all correspondence and requests for reprints to: Dr. Vivian Hwa, Department of Pediatrics, NRC5, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239-3098. E-mail: hwav{at}ohsu.edu.

Context: Among more than 250 cases of GH insensitivity syndrome (GHIS) reported to date, the largest cohort was identified in southern Ecuador. In the Ecuadorian GHIS cohort, a sense mutation (GAA > GAG) at codon E180 of GH receptor [GHR (E180sp)] results in deletion of codons 181–188. No functional studies of this mutation have been performed, nor have different mutations at codon 180 been reported.

Objective: We now report identification of a novel GHR mutation, also within codon E180, in two distantly related GHIS subjects of Inuit origin and provide mechanistic insights into the defects caused by the Inuit and Ecuadorian GHR mutations.

Patients: The two Inuit subjects, with heights of –5 SD score and –7 SD score, respectively, had elevated circulating levels of GH but low levels of GH-binding protein, IGF-I, and IGF-binding protein-3.

Results: Both Inuit subjects carry the same novel nonsense homozygous GHR mutation at codon E180 (GAA->TAA, E180X). In vitro reconstitution experiments demonstrated that GHR (E180sp), but not GHR (E180X), could be stably expressed. GHR (E180sp), however, could not bind GH and could neither activate signal transducer and activator of transcription-5b nor induce -5b-dependent gene expression on GH treatment. Furthermore, the GHR (E180sp), which has a deletion of eight amino acid residues within the GHR dimerization domain, although retaining the ability to homodimerize, was defective in trafficking to the cell surface.

Conclusions: The E180X mutation identified in two Inuit patients resulted in a truncated, unstably expressed GHR variant, whereas the E180 splicing mutation previously identified in the Ecuadorian cohort, affected both GH binding and GHR trafficking and rendered the abnormal GHR nonfunctional.