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
| Autor: | Peng Fang, Brian M. Little, Jaime Guevara-Aguirre, Vivian Hwa, Rose Girgis, Ron G. Rosenfeld, Katherine L. Pratt |
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| Rok vydání: | 2008 |
| Předmět: |
medicine.medical_specialty
Adolescent Endocrinology Diabetes and Metabolism Clinical Biochemistry Context (language use) Growth hormone receptor Biology Gene mutation medicine.disease_cause Biochemistry Cohort Studies Endocrinology Internal medicine medicine Humans Insulin-Like Growth Factor I Codon Receptor Gene Genetics Mutation Biochemistry (medical) Receptors Somatotropin Laron Syndrome Somatropin Inuit Child Preschool Cohort Female Dimerization hormones hormone substitutes and hormone antagonists |
| Zdroj: | The Journal of Clinical Endocrinology & Metabolism. 93:1030-1037 |
| ISSN: | 1945-7197 0021-972X |
| DOI: | 10.1210/jc.2007-2022 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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