Novel Dominant-Negative GH Receptor Mutations Expands the Spectrum of GHI and IGF-I Deficiency.
Por:
Vairamani K, Merjaneh L, Casano-Sancho P, Sanli ME, David A, Metherell LA, Savage MO, Del Pozo JS, Backeljauw PF, Rosenfeld RG, Aisenberg J, Dauber A and Hwa V
Publicada:
1 abr 2017
Ahead of Print:
8 mar 2017
Categoría:
Endocrinology, diabetes and metabolism
Resumen:
CONTEXT: Autosomal-recessive mutations in the growth hormone receptor (GHR) are the most common causes for primary growth hormone insensitivity (GHI) syndrome with classical GHI phenotypically characterized by severe short stature and marked insulin-like growth factor (IGF)-I deficiency. We report three families with dominant-negative heterozygous mutations in the intracellular domain of the GHR causing a nonclassical GHI phenotype. OBJECTIVE: To determine if the identified GHR heterozygous variants exert potential dominant-negative effects and are the cause for the GHI phenotype in our patients. RESULTS: All three mutations (c.964dupG, c.920_921insTCTCAAAGATTACA, and c.945+2T>C) are predicted to result in frameshift and early protein termination. In vitro functional analysis of variants c.964dupG and c.920_921insTCTCAAAGATTACA (c.920_921ins14) suggests that these variants are expressed as truncated proteins and, when coexpressed with wild-type GHR, mimicking the heterozygous state in our patients, exert dominant-negative effects. Additionally, we provide evidence that a combination therapy of recombinant human growth hormone (rhGH) and rhIGF-I improved linear growth to within normal range for one of our previously reported patients with a characterized, dominant-negative GHR (c.899dupC) mutation. CONCLUSION: Dominant-negative GHR mutations are causal of the mild GHI with substantial growth failure observed in our patients. Heterozygous defects in the intracellular domain of GHR should, therefore, be considered in cases of idiopathic short stature and IGF-I deficiency. Combination therapy of rhGH and rhIGF-I improved growth in one of our patients.
Filiaciones:
Vairamani K:
Cincinnati Center for Growth Disorders, Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229
Merjaneh L:
Division of Endocrinology Diabetes, Seattle Children's Hospital, Seattle, Washington 98105
Casano-Sancho P:
Division of Pediatric Endocrinology, Sant Joan de Déu Hospital, Center in Diabetes and Associated Metabolic Disorders, 08950 Barcelona, Spain
Sanli ME:
Cincinnati Center for Growth Disorders, Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229
David A:
Centre for Bioinformatics and System Biology, Department of Life Sciences, Imperial College London, London, SW7 2AZ, United Kingdom
Metherell LA:
Centre for Endocrinology, William Harvey Research Institute, John Vane Science Centre, Queen Mary, University of London, Charterhouse Square, London, EC1M 6BQ, United Kingdom
Savage MO:
Centre for Endocrinology, William Harvey Research Institute, John Vane Science Centre, Queen Mary, University of London, Charterhouse Square, London, EC1M 6BQ, United Kingdom
Del Pozo JS:
Pediatric Endocrinology and Dysmorphology Unit, Hospital 12 de Octubre, 28041 Madrid, Spain
Backeljauw PF:
Cincinnati Center for Growth Disorders, Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229
Rosenfeld RG:
Department of Pediatrics, Oregon Health Science University, Portland, Oregon 97239
Aisenberg J:
Pediatrics Endocrinology, Hackensack University Medical Center, Hackensack, New Jersey 07601
Dauber A:
Cincinnati Center for Growth Disorders, Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229
Hwa V:
Cincinnati Center for Growth Disorders, Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229
Open Access
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