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Partial Loss of Function of the GHRH Receptor Leads to Mild Growth Hormone Deficiency

Gregory, LC; Alatzoglou, KS; McCabe, MJ; Hindmarsh, PC; Saldanha, JW; Romano, N; Le Tissier, P; (2016) Partial Loss of Function of the GHRH Receptor Leads to Mild Growth Hormone Deficiency. Journal of Clinical Endocrinology and Metabolism , 101 (10) pp. 3608-3615. 10.1210/jc.2016-2254. Green open access

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Abstract

OBJECTIVE: Recessive mutations in GHRHR are associated with severe isolated growth hormone deficiency (IGHD), with a final height in untreated patients of 130 cm ± 10 cm (-7.2 ± 1.6 SDS; males) and 114 ± 0.7 cm (-8.3 ± 0.1 SDS; females). DESIGN: We hypothesized that a consanguineous Pakistani family with IGHD in three siblings (two males, one female) would have mutations in GH1 or GHRHR. RESULTS: Two novel homozygous missense variants [c.11G>A (p.R4Q), c.236C>T (p.P79L)] at conserved residues were identified in all three siblings. Both were absent from control databases, aside from pR4Q appearing once in heterozygous form in the Exome Aggregation Consortium Browser. The brothers were diagnosed with GH deficiency at 9.8 and 6.0 years (height SDS: -2.24 and -1.23, respectively), with a peak GH of 2.9 μg/liter with low IGF-1/IGF binding protein 3. Their sister presented at 16 years with classic GH deficiency (peak GH <0.1 μg/liter, IGF-1 <3.3 mmol/liter) and attained an untreated near-adult height of 144 cm (-3.0 SDS); the tallest untreated patient with GHRHR mutations reported. An unrelated Pakistani female IGHD patient was also compound homozygous. All patients had a small anterior pituitary on magnetic resonance imaging. Functional analysis revealed a 50% reduction in maximal cAMP response to stimulation with GHRH by the p.R4Q/p.P79L double mutant receptor, with a 100-fold increase in EC50. CONCLUSION: We report the first coexistence of two novel compound homozygous GHRHR variants in two unrelated pedigrees associated with a partial loss of function. Surprisingly, the patients have a relatively mild IGHD phenotype. Analysis revealed that the pP79L mutation is associated with the compromise in function, with the residual partial activity explaining the mild phenotype.

Type: Article
Title: Partial Loss of Function of the GHRH Receptor Leads to Mild Growth Hormone Deficiency
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1210/jc.2016-2254
Publisher version: http://doi.org/10.1210/jc.2016-2254
Language: English
Additional information: Copyright © 2016 by the Endocrine Society
Keywords: Phenotype magnetic resonance imaging mutation pituitary hormones, anterior somatotropin deficiency adult heterozygote homozygote insulin-like growth factor binding protein 3 insulin-like growth factor i genetic pedigree relationship - sibling cyclic amp growth hormone-releasing hormone receptor exome
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Genetics and Genomic Medicine Dept
URI: https://discovery.ucl.ac.uk/id/eprint/1508173
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