title: Partial Loss of Function of the GHRH Receptor Leads to Mild Growth Hormone Deficiency.
abstract: 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).
  
  
  
  We hypothesized that a consanguineous Pakistani family with IGHD in three siblings (two males, one female) would have mutations in GH1 or GHRHR.
  
  
  
  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.
  
  
  
  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.
authors: Section of Genetics and Epigenetics in Health and Disease (L.C.G., K.S.A., M.J.M., P.C.H., M.T.), Genetics and Genomic Medicine Programme, UCL Great Ormond Street Institute of Child Health, London, United Kingdom; Kinghorn Centre for Clinical Genomics (M.J.M.), Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; St Vincent's Clinical School (M.J.M.), UNSW Australia, Sydney, NSW, Australia; National Institute for Medical Research (J.W.S.), Mill Hill, London, United Kingdom; Centre for Integrative Physiology (N.R., P.L.T.), University of Edinburgh, Edinburgh, United Kingdom.
authors: Louise Cheryl
authors: LC
authors: Gregory
authors: Section of Genetics and Epigenetics in Health and Disease (L.C.G., K.S.A., M.J.M., P.C.H., M.T.), Genetics and Genomic Medicine Programme, UCL Great Ormond Street Institute of Child Health, London, United Kingdom; Kinghorn Centre for Clinical Genomics (M.J.M.), Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; St Vincent's Clinical School (M.J.M.), UNSW Australia, Sydney, NSW, Australia; National Institute for Medical Research (J.W.S.), Mill Hill, London, United Kingdom; Centre for Integrative Physiology (N.R., P.L.T.), University of Edinburgh, Edinburgh, United Kingdom.
authors: Kyriaki Sandy
authors: KS
authors: Alatzoglou
authors: Section of Genetics and Epigenetics in Health and Disease (L.C.G., K.S.A., M.J.M., P.C.H., M.T.), Genetics and Genomic Medicine Programme, UCL Great Ormond Street Institute of Child Health, London, United Kingdom; Kinghorn Centre for Clinical Genomics (M.J.M.), Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; St Vincent's Clinical School (M.J.M.), UNSW Australia, Sydney, NSW, Australia; National Institute for Medical Research (J.W.S.), Mill Hill, London, United Kingdom; Centre for Integrative Physiology (N.R., P.L.T.), University of Edinburgh, Edinburgh, United Kingdom.
authors: Mark James
authors: MJ
authors: McCabe
authors: Section of Genetics and Epigenetics in Health and Disease (L.C.G., K.S.A., M.J.M., P.C.H., M.T.), Genetics and Genomic Medicine Programme, UCL Great Ormond Street Institute of Child Health, London, United Kingdom; Kinghorn Centre for Clinical Genomics (M.J.M.), Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; St Vincent's Clinical School (M.J.M.), UNSW Australia, Sydney, NSW, Australia; National Institute for Medical Research (J.W.S.), Mill Hill, London, United Kingdom; Centre for Integrative Physiology (N.R., P.L.T.), University of Edinburgh, Edinburgh, United Kingdom.
authors: Peter Christopher
authors: PC
authors: Hindmarsh
authors: Section of Genetics and Epigenetics in Health and Disease (L.C.G., K.S.A., M.J.M., P.C.H., M.T.), Genetics and Genomic Medicine Programme, UCL Great Ormond Street Institute of Child Health, London, United Kingdom; Kinghorn Centre for Clinical Genomics (M.J.M.), Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; St Vincent's Clinical School (M.J.M.), UNSW Australia, Sydney, NSW, Australia; National Institute for Medical Research (J.W.S.), Mill Hill, London, United Kingdom; Centre for Integrative Physiology (N.R., P.L.T.), University of Edinburgh, Edinburgh, United Kingdom.
authors: Jose William
authors: JW
authors: Saldanha
authors: Section of Genetics and Epigenetics in Health and Disease (L.C.G., K.S.A., M.J.M., P.C.H., M.T.), Genetics and Genomic Medicine Programme, UCL Great Ormond Street Institute of Child Health, London, United Kingdom; Kinghorn Centre for Clinical Genomics (M.J.M.), Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; St Vincent's Clinical School (M.J.M.), UNSW Australia, Sydney, NSW, Australia; National Institute for Medical Research (J.W.S.), Mill Hill, London, United Kingdom; Centre for Integrative Physiology (N.R., P.L.T.), University of Edinburgh, Edinburgh, United Kingdom.
authors: Nicola
authors: N
authors: Romano
authors: Section of Genetics and Epigenetics in Health and Disease (L.C.G., K.S.A., M.J.M., P.C.H., M.T.), Genetics and Genomic Medicine Programme, UCL Great Ormond Street Institute of Child Health, London, United Kingdom; Kinghorn Centre for Clinical Genomics (M.J.M.), Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; St Vincent's Clinical School (M.J.M.), UNSW Australia, Sydney, NSW, Australia; National Institute for Medical Research (J.W.S.), Mill Hill, London, United Kingdom; Centre for Integrative Physiology (N.R., P.L.T.), University of Edinburgh, Edinburgh, United Kingdom.
authors: Paul
authors: P
authors: Le Tissier
authors: Section of Genetics and Epigenetics in Health and Disease (L.C.G., K.S.A., M.J.M., P.C.H., M.T.), Genetics and Genomic Medicine Programme, UCL Great Ormond Street Institute of Child Health, London, United Kingdom; Kinghorn Centre for Clinical Genomics (M.J.M.), Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; St Vincent's Clinical School (M.J.M.), UNSW Australia, Sydney, NSW, Australia; National Institute for Medical Research (J.W.S.), Mill Hill, London, United Kingdom; Centre for Integrative Physiology (N.R., P.L.T.), University of Edinburgh, Edinburgh, United Kingdom.
authors: Mehul Tulsidas
authors: MT
authors: Dattani
mesh_terms: D000293:Adolescent; D002648:Child; D003241:Consanguinity; D004393:Dwarfism, Pituitary / Q000235:genetics* / Q000503:physiopathology*; D005260:Female; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D010154:Pakistan; D010375:Pedigree; D010641:Phenotype; D018013:Receptors, Neuropeptide / Q000235:genetics*; D018017:Receptors, Pituitary Hormone-Regulating Hormone / Q000235:genetics*
chemical_list: D018013:Receptors, Neuropeptide; D018017:Receptors, Pituitary Hormone-Regulating Hormone; C048250:somatotropin releasing hormone receptor