Obesity-Associated GNAS Mutations and the Melanocortin Pathway.

BACKGROUND GNAS encodes the Gαs (stimulatory G-protein alpha subunit) protein, which mediates G protein-coupled receptor (GPCR) signaling. GNAS mutations cause developmental delay, short stature, and skeletal abnormalities in a syndrome called Albright's hereditary osteodystrophy. Because of imprinting, mutations on the maternal allele also cause obesity and hormone resistance (pseudohypoparathyroidism). METHODS We performed exome sequencing and targeted resequencing in 2548 children who presented with severe obesity, and we unexpectedly identified 22 GNAS mutation carriers. We investigated whether the effect of GNAS mutations on melanocortin 4 receptor (MC4R) signaling explains the obesity and whether the variable clinical spectrum in patients might be explained by the results of molecular assays. RESULTS Almost all GNAS mutations impaired MC4R signaling. A total of 6 of 11 patients who were 12 to 18 years of age had reduced growth. In these patients, mutations disrupted growth hormone-releasing hormone receptor signaling, but growth was unaffected in carriers of mutations that did not affect this signaling pathway (mean standard-deviation score for height, -0.90 vs. 0.75, respectively; P = 0.02). Only 1 of 10 patients who reached final height before or during the study had short stature. GNAS mutations that impaired thyrotropin receptor signaling were associated with developmental delay and with higher thyrotropin levels (mean [±SD], 8.4±4.7 mIU per liter) than those in 340 severely obese children who did not have GNAS mutations (3.9±2.6 mIU per liter; P = 0.004). CONCLUSIONS Because pathogenic mutations may manifest with obesity alone, screening of children with severe obesity for GNAS deficiency may allow early diagnosis, improving clinical outcomes, and melanocortin agonists may aid in weight loss. GNAS mutations that are identified by means of unbiased genetic testing differentially affect GPCR signaling pathways that contribute to clinical heterogeneity. Monogenic diseases are clinically more variable than their classic descriptions suggest. (Funded by Wellcome and others.).

[1]  W. Chung,et al.  Efficacy and safety of setmelanotide, an MC4R agonist, in individuals with severe obesity due to LEPR or POMC deficiency: single-arm, open-label, multicentre, phase 3 trials. , 2020, The lancet. Diabetes & endocrinology.

[2]  E. Zeggini,et al.  Exome Sequencing Identifies Genes and Gene Sets Contributing to Severe Childhood Obesity, Linking PHIP Variants to Repressed POMC Transcription , 2020, Cell metabolism.

[3]  E. Germain-Lee Management of pseudohypoparathyroidism , 2019, Current opinion in pediatrics.

[4]  Matthew W. Darlison,et al.  Rare single gene disorders: estimating baseline prevalence and outcomes worldwide , 2018, Journal of Community Genetics.

[5]  H. Jüppner,et al.  Genetic and Epigenetic Defects at the GNAS Locus Lead to Distinct Patterns of Skeletal Growth but Similar Early‐Onset Obesity , 2018, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[6]  O. Mäkitie,et al.  Diagnosis and management of pseudohypoparathyroidism and related disorders: first international Consensus Statement , 2018, Nature Reviews Endocrinology.

[7]  K. Clément,et al.  MC4R agonism promotes durable weight loss in patients with leptin receptor deficiency , 2018, Nature Medicine.

[8]  Amita Sharma,et al.  Early-Onset Obesity: Unrecognized First Evidence for GNAS Mutations and Methylation Changes , 2017, The Journal of clinical endocrinology and metabolism.

[9]  K. Clément,et al.  Evaluation of a melanocortin-4 receptor (MC4R) agonist (Setmelanotide) in MC4R deficiency , 2017, Molecular metabolism.

[10]  Tom R. Gaunt,et al.  Rare Variant Analysis of Human and Rodent Obesity Genes in Individuals with Severe Childhood Obesity , 2017, Scientific Reports.

[11]  A. Mamoune,et al.  Progressive Development of PTH Resistance in Patients With Inactivating Mutations on the Maternal Allele of GNAS , 2017, The Journal of clinical endocrinology and metabolism.

[12]  M. Bastepe,et al.  Heterotrimeric G proteins in the control of parathyroid hormone actions. , 2017, Journal of molecular endocrinology.

[13]  H. Jüppner,et al.  Pseudohypoparathyroidism: one gene, several syndromes , 2017, Journal of Endocrinological Investigation.

[14]  P. Hindmarsh,et al.  Pseudohypoparathyroidism Type 1A-Subclinical Hypothyroidism and Rapid Weight Gain as Early Clinical Signs: A Clinical Review of 10 Cases , 2016, Journal of clinical research in pediatric endocrinology.

[15]  K. Clément,et al.  Proopiomelanocortin Deficiency Treated with a Melanocortin-4 Receptor Agonist. , 2016, The New England journal of medicine.

[16]  K. Okamura,et al.  Complex Genomic Rearrangement Within the GNAS Region Associated With Familial Pseudohypoparathyroidism Type 1b. , 2016, The Journal of clinical endocrinology and metabolism.

[17]  A. Linglart,et al.  The Prevalence of GNAS Deficiency-Related Diseases in a Large Cohort of Patients Characterized by the EuroPHP Network. , 2016, The Journal of clinical endocrinology and metabolism.

[18]  B. Zemel,et al.  Resting Energy Expenditure Is Decreased in Pseudohypoparathyroidism Type 1A. , 2016, The Journal of clinical endocrinology and metabolism.

[19]  Bale,et al.  Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology , 2015, Genetics in Medicine.

[20]  R. Thakker,et al.  GNAS Mutations in Pseudohypoparathyroidism Type 1a and Related Disorders , 2014, Human mutation.

[21]  H. Jüppner,et al.  Functional characterization of GNAS mutations found in patients with pseudohypoparathyroidism type Ic defines a new subgroup of pseudohypoparathyroidism affecting selectively Gsα‐receptor interaction , 2011, Human mutation.

[22]  S. O’Rahilly,et al.  Obesity due to melanocortin 4 receptor (MC4R) deficiency is associated with increased linear growth and final height, fasting hyperinsulinemia, and incompletely suppressed growth hormone secretion. , 2011, The Journal of clinical endocrinology and metabolism.

[23]  S. Mackem,et al.  Parathyroid hormone/parathyroid hormone-related protein receptor signaling is required for maintenance of the growth plate in postnatal life , 2010, Proceedings of the National Academy of Sciences.

[24]  O. Gavrilova,et al.  Central nervous system imprinting of the G protein G(s)alpha and its role in metabolic regulation. , 2009, Cell metabolism.

[25]  M. Maghnie,et al.  Genetic analysis and evaluation of resistance to thyrotropin and growth hormone-releasing hormone in pseudohypoparathyroidism type Ib. , 2007, The Journal of clinical endocrinology and metabolism.

[26]  L. Weinstein,et al.  Stimulatory G protein directly regulates hypertrophic differentiation of growth plate cartilage in vivo. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[27]  M. Levine,et al.  Growth hormone deficiency in pseudohypoparathyroidism type 1a: another manifestation of multihormone resistance. , 2003, The Journal of clinical endocrinology and metabolism.

[28]  Tim Cheetham,et al.  Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. , 2003, The New England journal of medicine.

[29]  M. Saji,et al.  Paternal imprinting of Galpha(s) in the human thyroid as the basis of TSH resistance in pseudohypoparathyroidism type 1a. , 2002, Biochemical and biophysical research communications.

[30]  A. Grüters,et al.  Thyroid Function and Obesity in Children and Adolescents , 2001, Hormone Research in Paediatrics.

[31]  P. Bougnères,et al.  The Journal of Clinical Endocrinology & Metabolism Printed in U.S.A. Copyright © 1999 by The Endocrine Society Resistance to the Lipolytic Action of Epinephrine: A New Feature of Protein G s Deficiency , 1999 .

[32]  T J Cole,et al.  British 1990 growth reference centiles for weight, height, body mass index and head circumference fitted by maximum penalized likelihood. , 1998, Statistics in medicine.

[33]  R. Lasker,et al.  Resistance to multiple hormones in patients with pseudohypoparathyroidism. Association with deficient activity of guanine nucleotide regulatory protein. , 1983, The American journal of medicine.

[34]  S. O’Rahilly,et al.  Modulation of blood pressure by central melanocortinergic pathways. , 2009, The New England journal of medicine.

[35]  L. Weinstein,et al.  The stimulatory G protein alpha-subunit Gs alpha is imprinted in human thyroid glands: implications for thyroid function in pseudohypoparathyroidism types 1A and 1B. , 2003, The Journal of clinical endocrinology and metabolism.

[36]  Min Chen,et al.  Gs(alpha) mutations and imprinting defects in human disease. , 2002, Annals of the New York Academy of Sciences.

[37]  L. Weinstein,et al.  Receptor-mediated adenylyl cyclase activation through XLalpha(s), the extra-large variant of the stimulatory G protein alpha-subunit. , 2002, Molecular endocrinology.

[38]  D. Accili,et al.  Variable and tissue-specific hormone resistance in heterotrimeric Gs protein alpha-subunit (Gsalpha) knockout mice is due to tissue-specific imprinting of the gsalpha gene. , 1998, Proceedings of the National Academy of Sciences of the United States of America.