Skip to main content
SpringerLink
Log in
Book cover

Pharmacogenomics in Drug Discovery and Development pp 153–187Cite as

G Protein-Coupled Receptor Mutations and Human Genetic Disease

  • Protocol
  • First Online:

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1175))

Abstract

Genetic variations in G protein-coupled receptor genes (GPCRs) disrupt GPCR function in a wide variety of human genetic diseases. In vitro strategies and animal models have been used to identify the molecular pathologies underlying naturally occurring GPCR mutations. Inactive, overactive, or constitutively active receptors have been identified that result in pathology. These receptor variants may alter ligand binding, G protein coupling, receptor desensitization and receptor recycling. Receptor systems discussed include rhodopsin, thyrotropin, parathyroid hormone, melanocortin, follicle-stimulating hormone (FSH), luteinizing hormone, gonadotropin-releasing hormone (GNRHR), adrenocorticotropic hormone, vasopressin, endothelin-β, purinergic, and the G protein associated with asthma (GPRA or neuropeptide S receptor 1 (NPSR1)). The role of activating and inactivating calcium-sensing receptor (CaSR) mutations is discussed in detail with respect to familial hypocalciuric hypercalcemia (FHH) and autosomal dominant hypocalemia (ADH). The CASR mutations have been associated with epilepsy. Diseases caused by the genetic disruption of GPCR functions are discussed in the context of their potential to be selectively targeted by drugs that rescue altered receptors. Examples of drugs developed as a result of targeting GPCRs mutated in disease include: calcimimetics and calcilytics, therapeutics targeting melanocortin receptors in obesity, interventions that alter GNRHR loss from the cell surface in idiopathic hypogonadotropic hypogonadism and novel drugs that might rescue the P2RY12 receptor congenital bleeding phenotype. De-orphanization projects have identified novel disease-associated receptors, such as NPSR1 and GPR35. The identification of variants in these receptors provides genetic reagents useful in drug screens. Discussion of the variety of GPCRs that are disrupted in monogenic Mendelian disorders provides the basis for examining the significance of common pharmacogenetic variants.

This is a preview of subscription content, log in via an institution.

Protocol
USD   49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Springer Nature is developing a new tool to find and evaluate Protocols. Learn more

References

  1. Spiegel AM (1998) Introduction to G-protein-coupled signal transduction and human disease. In: Spiegel AM (ed) G proteins, receptors, and disease. Humana, Totowa, NJ, pp 1–21

    Google Scholar 

  2. Thompson MD, Siminovitch KA, Cole DE (2008) G Protein-coupled receptor pharmacogenetics. Methods Mol Biol 448:139–185

    CAS  PubMed  Google Scholar 

  3. Thompson MD, Burnham WM, Cole DE (2005) The G protein-coupled receptors: pharmacogenetics and disease. Crit Rev Clin Lab Sci 42:311–392

    CAS  PubMed  Google Scholar 

  4. Tan CM, Brady AE, Nickols HH et al (2004) Membrane trafficking of G protein-coupled receptors. Annu Rev Pharmacol Toxicol 44:559–609

    CAS  PubMed  Google Scholar 

  5. Thompson MD, Percy ME, Burnham WM et al (2008) G Protein-coupled receptors disrupted in human genetic disease. Methods Mol Biol 448:109–138

    CAS  PubMed  Google Scholar 

  6. Milligan G, Stevens PA, Ramsay D et al (2002) Ligand rescue of constitutively active mutant receptors. Neurosignals 11:29–33

    CAS  PubMed  Google Scholar 

  7. Seifert R, Wenzel-Seifert K (2002) Constitutive activity of G-protein-coupled receptors: cause of disease and common property of wild-type receptors. Naunyn-Schmiedeberg Arch Pharmacol 366:381–416

    CAS  Google Scholar 

  8. Thompson MD, Capra V, Takasaki J et al (2007) A functional G300S variant of the cysteinyl leukotriene 1 receptor is associated with atopy in a Tristan da Cunha isolate. Pharmacogenet Genomics 17:539–549

    CAS  PubMed  Google Scholar 

  9. Thompson MD, Gravesandeg KSV, Galczenski H et al (2003) A cysteinyl leukotriene 2 receptor variant is associated with atopy in the population of Tristan da Cunha. Pharmacogenetics 13:641–649

    CAS  PubMed  Google Scholar 

  10. Thompson MD, Takasaki J, Capra V et al (2006) G-protein-coupled receptors and asthma endophenotypes: the cysteinyl leukotriene system in perspective. Mol Diagn Ther 10:353–366

    CAS  PubMed  Google Scholar 

  11. Daiger SP, Sullivan LS, Bowne SJ (2013) Genes and mutations causing retinitis pigmentosa. Clin Genet 84:132–141

    CAS  PubMed  Google Scholar 

  12. Thompson MD, Cole DE, Jose P (2008) The pharmacogenomics of G protein-coupled receptor signaling: insight from health and disease. Methods Mol Biol 448:77–108

    CAS  PubMed  Google Scholar 

  13. Almaghtheh M, Gregory C, Inglehearn C et al (1993) Rhodopsin mutations in autosomal-dominant retinitis-pigmentosa. Hum Mutat 2:249–255

    CAS  Google Scholar 

  14. Rim J, Oprian DD (1995) Constitutive activation of opsin—interaction of mutants with rhodopsin kinase and arrestin. Biochemistry 34:11938–11945

    CAS  PubMed  Google Scholar 

  15. Sullivan JM, Scott KM, Falls HF et al (1993) A novel rhodopsin mutation at the retinal binding-site (Lys-296-Met) in Adrp. Invest Ophthalmol Vis Sci 34:1149

    Google Scholar 

  16. Bunge S, Wedemann H, David D et al (1993) Molecular analysis and genetic-mapping of the rhodopsin gene in families with autosomal-dominant retinitis-pigmentosa. Genomics 17:230–233

    CAS  PubMed  Google Scholar 

  17. Farrar GJ, Mcwilliam P, Bradley DG et al (1990) Autosomal dominant retinitis-pigmentosa—linkage to rhodopsin and evidence for genetic-heterogeneity. Genomics 8:35–40

    CAS  PubMed  Google Scholar 

  18. Inglehearn CF, Lester DH, Bashir R et al (1992) Recombination between rhodopsin and locus D3S47 (C17) in rhodopsin retinitis-pigmentosa families. Am J Hum Genet 50:590–597

    CAS  PubMed Central  PubMed  Google Scholar 

  19. Neidhardt J, Barthelmes D, Farahmand F et al (2006) Different amino acid substitutions at the same position in rhodopsin lead to distinct phenotypes. Invest Ophthalmol Vis Sci 47:1630–1635

    PubMed  Google Scholar 

  20. Andres A, Kosoy A, Garriga P et al (2001) Mutations at position 125 in transmembrane helix III of rhodopsin affect the structure and signalling of the receptor. Eur J Biochem 268:5696–5704

    CAS  PubMed  Google Scholar 

  21. Andreoli TE (1998) Diseases of receptors: introductory comments. Am J Med 105:242–243

    CAS  PubMed  Google Scholar 

  22. Huang L, Li W, Tang W et al (2012) A Chinese family with Oguchi’s disease due to compound heterozygosity including a novel deletion in the arrestin gene. Mol Vis 18:528–536

    CAS  PubMed Central  PubMed  Google Scholar 

  23. Fuchs S, Nakazawa M, Maw M et al (1995) A homozygous 1-base pair deletion in the arrestin gene is a frequent cause of Oguchi disease in Japanese. Nat Genet 10:360–362

    CAS  PubMed  Google Scholar 

  24. Duprez L, Parma J, Vansande J et al (1994) Germline mutations in the thyrotropin receptor gene cause non-autoimmune autosomal-dominant hyperthyroidism. Nat Genet 7:396–401

    CAS  PubMed  Google Scholar 

  25. Arturi F, Capula C, Chiefari E et al (1998) Thyroid hyperfunctioning adenomas with and without Gsp/TSH receptor mutations show similar clinical features. Exp Clin Endocrinol Diabetes 106:234–236

    CAS  PubMed  Google Scholar 

  26. Kaczur V, Takacs M, Szalai C et al (2000) Analysis of the genetic variability of the 1st (CCC/ACC, P52T) and the 10th exons (bp 1012–1704) of the TSH receptor gene in Graves’ disease. Eur J Immunogenet 27:17–23

    CAS  PubMed  Google Scholar 

  27. Biebermann H, Schoneberg T, Hess C et al (2001) The first activating TSH receptor mutation in transmembrane domain 1 identified in a family with nonautoimmune hyperthyroidism. J Clin Endocrinol Metab 86:4429–4433

    CAS  PubMed  Google Scholar 

  28. Jordan N, Williams N, Gregory JW et al (2003) The W546X mutation of the thyrotropin receptor gene: potential major contributor to thyroid dysfunction in a Caucasian population. J Clin Endocrinol Metab 88:1002–1005

    CAS  PubMed  Google Scholar 

  29. Biebermann H, Winkler F, Kleinau G (2010) Genetic defects, thyroid growth and malfunctions of the TSHR in pediatric patients. Front Biosci (Landmark Ed) 15:913–933

    CAS  Google Scholar 

  30. Hébrant A, Van Staveren WCG, Maenhaut C et al (2011) Genetic hyperthyroidism: hyperthyroidism due to activating TSHR mutations. Eur J Endocrinol 164:1–9

    PubMed  Google Scholar 

  31. Gabriel EM, Bergert ER, Grant CS et al (1999) Germline polymorphism of codon 727 of human thyroid-stimulating hormone receptor is associated with toxic multinodular goiter. J Clin Endocrinol Metab 84:3328–3335

    CAS  PubMed  Google Scholar 

  32. Biebermann H, Schoneberg T, Krude H et al (2000) Constitutively activating TSH-receptor mutations as a molecular cause of non-autoimmune hyperthyroidism in childhood. Arch Surg 385:390–392

    CAS  Google Scholar 

  33. Karges B, Krause G, Homoki J et al (2005) TSH receptor mutation V509A causes familial hyperthyroidism by release of interhelical constraints between transmembrane helices TMH3 and TMH5. J Endocrinol 186:377–385

    CAS  PubMed  Google Scholar 

  34. Tonacchera M, Agretti P, Chiovato L et al (2000) Activating thyrotropin receptor mutations are present in nonadenomatous hyperfunctioning nodules of toxic or autonomous multinodular goiter. J Clin Endocrinol Metab 85:2270–2274

    CAS  PubMed  Google Scholar 

  35. Lueblinghoff J, Eszlinger M, Jaeschke H et al (2011) Shared sporadic and somatic thyrotropin receptor mutations display more active in vitro activities than familial thyrotropin receptor mutations. Thyroid 21:221–229

    CAS  PubMed  Google Scholar 

  36. Pohlenz J, Pfarr N, Kruger S et al (2006) Subclinical hyperthyroidism due to a thyrotropin receptor (TSHR) gene mutation (S505R). Acta Paediatr 95:1685–1687

    PubMed  Google Scholar 

  37. Kaczur V, Puskas LG, Takacs M et al (2003) Evolution of the thyrotropin receptor: a G protein coupled receptor with an intrinsic capacity to dimerize. Mol Genet Metab 78:275–290

    CAS  PubMed  Google Scholar 

  38. Boelen A, Kwakkel J, Fliers E (2012) Thyroid hormone receptors in health and disease. Minerva Endocrinol 37:291–304

    CAS  PubMed  Google Scholar 

  39. Yun FH, Wong BY, Chase M et al (2007) Genetic variation at the calcium-sensing receptor (CASR) locus: implications for clinical molecular diagnostics. Clin Biochem Biochem 40:551–556

    CAS  Google Scholar 

  40. Gunn IR, Gaffney D (2004) Clinical and laboratory features of calcium-sensing receptor disorders: a systematic review. Ann Clin Biochem 41:441–458

    CAS  PubMed  Google Scholar 

  41. Brown EM (2007) Clinical lessons from the calcium-sensing receptor. Nat Clin Pract Endocrinol Metab 3:122–133

    CAS  PubMed  Google Scholar 

  42. Hendy GN, Guarnieri V, Canaff L (2009) Calcium-sensing receptor and associated diseases. Prog Mol Biol Transl Sci 89:31–95

    CAS  PubMed  Google Scholar 

  43. Scillitani A, Guarnieri V, De Geronimo S et al (2004) Blood ionized calcium is associated with clustered polymorphisms in the carboxy-terminal tail of the calcium-sensing receptor gene. J Clin Endocrinol Metab 89:5634–5638

    CAS  PubMed  Google Scholar 

  44. Scillitani A, Guarnieri V, Battista C et al (2007) Primary hyperparathyroidism and the presence of kidney stones are associated with different haplotypes of the calcium-sensing receptor. J Clin Endocrinol Metab 92:277–283

    CAS  PubMed  Google Scholar 

  45. O’Seaghdha CM, Yang Q, Glazer NL et al (2010) Common variants in the calcium-sensing receptor gene are associated with total serum calcium levels. Hum Mol Genet 19:4296–4303

    PubMed Central  PubMed  Google Scholar 

  46. Kapur K, Johnson T, Beckmann ND et al (2010) Genome-wide meta-analysis for serum calcium identifies significantly associated SNPs near the calcium-sensing gene. PLoS Genet 6:e1001035

    PubMed Central  PubMed  Google Scholar 

  47. Hendy GN, Canaff L, Cole DEC (2013) The CASR gene: alternative splicing and transcriptional control, and calcium-sensing receptor (CaSR) protein: structure and ligand binding sites. Best Pract Res Clin Endocrinol Metab 27:285–301

    CAS  PubMed  Google Scholar 

  48. Hannan FM, Nesbit MA, Zhang C et al (2012) Identification of 70 calcium-sensing receptor mutations in hyper- and hypo-calcemic patients: evidence for clustering of extracellular domain mutations at calcium-binding sites. Hum Mol Genet 21:2768–2778

    CAS  PubMed  Google Scholar 

  49. Guarnieri V, Canaff L, Yun FHJ et al (2010) Calcium-sensing receptor (CASR) mutations in hypercalcemic states: studies from a single endocrine clinic over three years. J Clin Endocrinol Metab 95:1819–1829

    CAS  PubMed  Google Scholar 

  50. Christensen SE, Nissen PH, Vestergaard P et al (2011) Familial hypocalciuric hypercalcaemia: a review. Curr Opin Endocrinol Diabetes Obes 18:359–370

    CAS  PubMed  Google Scholar 

  51. Cole DEC, Janicic N, Salisbury SR et al (1997) Neonatal severe hyperparathyroidism, secondary hyperparathyroidism, and familial hypocalciuric hypercalcemia: multiple different phenotypes associated with an inactivating Alu insertion mutation of the calcium-sensing receptor (CASR) gene. Am J Med Genet 71:202–210

    CAS  PubMed  Google Scholar 

  52. Nesbit MA, Hannan FM, Howles SA et al (2013) Mutations affecting G-protein subunit α11 in hypercalcemia and hypocalcemia. N Engl J Med 368:2476–2486

    CAS  PubMed Central  PubMed  Google Scholar 

  53. Cheung R, Erclik MS, Mitchell J (2005) Increased expression of G11alpha in osteoblastic cells enhances parathyroid hormone activation of phospholipase C and AP-1 regulation of matrix metalloproteinase-13 mRNA. J Cell Physiol 204:336–343

    CAS  PubMed  Google Scholar 

  54. Hendy GN, Cole DEC (2013) Ruling in a suspect: the role of AP2S1 mutations in familial hypocalciuric hypercalcemia type 3. J Clin Endocrinol Metab 98(12):4666–4669

    CAS  PubMed  Google Scholar 

  55. Lienhardt A, Bai M, Lagarde JP et al (2001) Activating mutations of the calcium-sensing receptor: management of hypocalcemia. J Clin Endocrinol Metab 86:5313–5323

    CAS  PubMed  Google Scholar 

  56. Hendy GN, Minutti C, Canaff L et al (2003) Recurrent familial hypocalcemia due to germline mosaicism for an activating mutation of the calcium-sensing receptor gene. J Clin Endocrinol Metab 88:3674–3681

    CAS  PubMed  Google Scholar 

  57. Burren CP, Curley A, Christie P et al (2005) A family with autosomal dominant hypocalcaemia with hypercalciuria (ADHH): mutational analysis, phenotypic variability and treatment challenges. J Pediatr Endocrinol Metab 18:9–99

    Google Scholar 

  58. Kapoor A, Satishchandra P, Ratnapriya R et al (2008) An idiopathic epilepsy syndrome linked to 3q13.3-q21 and missense mutations in the extracellular calcium-sensing receptor gene. Ann Neurol 64:158–167

    CAS  PubMed  Google Scholar 

  59. Stepanchick A, McKenna J, McGovern O et al (2010) Calcium-sensing receptor mutations implicated in pancreatitis and idiopathic epilepsy syndrome disrupt an arginine-rich retention motif. Cell Physiol Biochem 26:363–374

    CAS  PubMed Central  PubMed  Google Scholar 

  60. Mannstadt M, Bravenboer B, Chitturi S et al (2013) Germline mutations affecting Gα11 in hypoparathyroidism. N Engl J Med 368:2532–2534

    CAS  PubMed Central  PubMed  Google Scholar 

  61. Scillitani A, Jang C, Wong BYL et al (2008) A functional polymorphism in the PTHR1 promoter region is associated with adult height and BMD measured at the femoral neck in a large cohort of young Caucasian women. Hum Genet 119:416–421

    Google Scholar 

  62. Calvi LM, Svhipani E (2000) The PTH/PTHrP receptor in Jansen’s metaphyseal chondrodysplasia. J Endocrinol Invest 23:545–554

    CAS  PubMed  Google Scholar 

  63. Jobert AS, Zhang P, Couvineau A et al (1998) Absence of functional receptors for parathyroid hormone and parathyroid hormone-related peptide in Blomstrand chondrodysplasia. J Clin Invest 102:34–40

    CAS  PubMed Central  PubMed  Google Scholar 

  64. Hoogendam J, Farih-Sips H, Wynaendts LC et al (2007) Novel mutations in the parathyroid hormone (PTH)/PTH-related peptide receptor type 1 causing Blomstrand osteochondrodysplasia types I and II. J Clin Endocrinol Metab 92:1088–1095

    CAS  PubMed  Google Scholar 

  65. Duchalet S, Ostergaard E, Cortes D et al (2005) Recessive mutations in PTHR1 cause contrasting skeletal dysplasias in Eiken and Blomstrand syndromes. Hum Mol Genet 14:1–5

    Google Scholar 

  66. Couvineau A, Wouters V, Bertrand G et al (2008) PTHR1 mutations associated with Ollier disease result in receptor loss of function. Hum Mol Genet 17:2766–2775

    CAS  PubMed Central  PubMed  Google Scholar 

  67. Collinson M, Leonard SJ, Charlton J et al (2010) Symmetrical enchondromatosis is associated with duplication of 12p11.23 to 12p11.22 including PTHLH. Am J Med Genet A 152A:3124–3128

    PubMed  Google Scholar 

  68. Yamaguchi T, Hosomichi K, Narita A et al (2011) Exome resequencing combined with linkage analysis identifies novel PTHR1 variants in primary failure of tooth eruption in Japanese. J Bone Miner Res 26:1655–1661

    CAS  PubMed  Google Scholar 

  69. Roth H, Fritsche LG, Meier C et al (2014) Expanding the spectrum of PTHR1 mutations in patients with primary failure of tooth eruption. Clin Oral Investig 18(2):377–384

    PubMed  Google Scholar 

  70. Kokkotou EG, Tritos NA, Mastaitis JW et al (2001) Melanin-concentrating hormone receptor is a target of leptin action in the mouse brain. Endocrinology 142:680–686

    CAS  PubMed  Google Scholar 

  71. Segal-Lieberman G, Bradley RL, Kokkotou E et al (2003) Melanin-concentrating hormone is a critical mediator of the leptin-deficient phenotype. Proc Natl Acad Sci U S A 100:10085–10090

    CAS  PubMed Central  PubMed  Google Scholar 

  72. Segal-Lieberman G, Trombly DJ, Juthani V et al (2003) NPY ablation in C57BL/6 mice leads to mild obesity and to an impaired refeeding response to fasting. Am J Physiol Endocrinol Metab 284:E1131–E1139

    CAS  PubMed  Google Scholar 

  73. Xu YL, Jackson VR, Civelli O (2004) Orphan G protein-coupled receptors and obesity. Eur J Pharmacol 500:243–253

    CAS  PubMed  Google Scholar 

  74. Vaisse C, Clement K, Guy-Grand B et al (1998) A frameshift mutation in human MC4R is associated with a dominant form of obesity. Nat Genet 20:113–114

    CAS  PubMed  Google Scholar 

  75. Lubrano-Berthelier C, Le Stunff C, Bougneres P et al (2004) Clinical case seminar—a homozygous null mutation delineates the role of the melanocortin-4 receptor in humans. J Clin Endocrinol Metab 89:2028–2032

    CAS  PubMed  Google Scholar 

  76. Yeo GSH, Farooqi IS, Aminian S et al (1998) A frameshift mutation in MC4R associated with dominantly inherited human obesity. Nat Genet 20:111–112

    CAS  PubMed  Google Scholar 

  77. Yeo GSH, Farooqi IS, Challis BG et al (2000) The role of melanocortin signalling in the control of body weight: evidence from human and murine genetic models. Q J Roy Meteorol Soc 93:7–14

    CAS  Google Scholar 

  78. Yeo GSH, Lank EJ, Farooqi IS et al (2003) Mutations in the human melanocortin-4 receptor gene associated with severe familial obesity disrupts receptor function through multiple molecular mechanisms. Hum Mol Genet 12:561–574

    CAS  PubMed  Google Scholar 

  79. Lubrano-Berthelier C, Cavazos M, Lestunff C et al (2003) Mutations in the transcriptionally essential region of the MC4R promoter are not a cause of severe obesity in humans. Diabetes 52:A397

    Google Scholar 

  80. O’Rahilly S, Yeo GSH, Farooqi IS (2004) Melanocortin receptors weigh in. Nat Med 10:351–352

    PubMed  Google Scholar 

  81. Adan RAH, Kas MJH (2003) Inverse agonism gains weight. Trends Pharmacol Sci 24:315–321

    CAS  PubMed  Google Scholar 

  82. Marsh DJ, Hollopeter G, Huszar D et al (1999) Response of melanocortin-4 receptor-deficient mice to anorectic and orexigenic peptides. Nat Genet 21:119–122

    CAS  PubMed  Google Scholar 

  83. Ste Marie L, Miura GI, Marsh DJ et al (2000) A metabolic defect promotes obesity in mice lacking melanocortin-4 receptors. Proc Natl Acad Sci U S A 97:12339–12344

    CAS  PubMed Central  PubMed  Google Scholar 

  84. Branson R, Potoczna N, Kral JG et al (2003) Binge eating as a major phenotype of melanocortin 4 receptor gene mutations. N Engl J Med 348:1096–1103

    CAS  PubMed  Google Scholar 

  85. List JF, Habener JF (2003) Defective melanocortin 4 receptors in hyperphagia and morbid obesity. N Engl J Med 348:1160–1163

    PubMed  Google Scholar 

  86. Farooqi IS, Keogh JM, Yeo GSH et al (2003) Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. N Engl J Med 348:1085–1095

    CAS  PubMed  Google Scholar 

  87. Vaisse C, Clement K, Durand E et al (2000) Melanocortin-4 receptor mutations are a frequent and heterogeneous cause of morbid obesity. J Clin Invest 106:253–262

    CAS  PubMed Central  PubMed  Google Scholar 

  88. Kuklish SL, Backer RT, Briner K et al (2006) Privileged structure based ligands for melanocortin receptors—4,4-disubstituted piperidine derivatives. Bioorg Med Chem Lett 16:3843–3846

    CAS  PubMed  Google Scholar 

  89. Nargund RP, Strack AM, Fong TM (2006) Melanocortin-4 receptor (MC4R) agonists for the treatment of obesity. J Med Chem 49:4035–4043

    CAS  PubMed  Google Scholar 

  90. Jiang W, Tucci FC, Chen CW et al (2006) Arylpropionylpiperazines as antagonists of the human melanocortin-4 receptor. Bioorg Med Chem Lett 16:4674–4678

    CAS  PubMed  Google Scholar 

  91. Piechowski CL, Rediger A, Lagemann C et al (2013) Inhibition of melanocortin-4 receptor dimerization by substitutions in intracellular loop 2. J Mol Endocrinol 51:109–118

    CAS  PubMed  Google Scholar 

  92. Gromoll J, Simoni M, Nordhoff V et al (1996) Functional and clinical consequences of mutations in the FSH receptor. Mol Cell Endocrinol 125:177–182

    CAS  PubMed  Google Scholar 

  93. Simoni M, Nieschlag E, Gromoll J (2002) Isoforms and single nucleotide polymorphisms of the FSH receptor gene: implications for human reproduction. Hum Reprod Update 8:413–421

    CAS  PubMed  Google Scholar 

  94. Laven JSE, Mulders AGMG, Suryandari DA et al (2003) Follicle-stimulating hormone receptor polymorphisms in women with normogonadotropic anovulatory infertility. Fertil Steril 80:986–992

    PubMed  Google Scholar 

  95. Gromoll J, Simoni M, Nieschlag E (1996) An activating mutation of the follicle-stimulating hormone receptor autonomously sustains spermatogenesis in a hypophysectomized man. J Clin Endocrinol Metab 81:1367–1370

    CAS  PubMed  Google Scholar 

  96. Ulloa-Aguirre A, Zariñán T, Dias JA et al (2014) Mutations in G protein-coupled receptors that impact receptor trafficking and reproductive function. Mol Cell Endocrinol 382(1):411–423. doi:10.1016/j.mce.2013.06.024

    CAS  PubMed  Google Scholar 

  97. Simoni M, Weinbauer GF, Gromoll J et al (1999) Role of FSH in male gonadal function. Ann Endocrinol (Paris) 60:102–106

    CAS  Google Scholar 

  98. De LA, Montanelli L, Van DJ et al (2006) Presence and absence of follicle-stimulating hormone receptor mutations provide some insights into spontaneous ovarian hyperstimulation syndrome physiopathology. J Clin Endocrinol Metab 91:555–562

    Google Scholar 

  99. Meehan TP, Narayan P (2007) Constitutively active luteinizing hormone receptors: consequences of in vivo expression. Mol Cell Endocrinol 260–262:294–300

    PubMed Central  PubMed  Google Scholar 

  100. Iiri T, Herzmark P, Nakamoto JM et al (1994) Rapid Gdp release from G(S-alpha) in patients with gain and loss of endocrine function. Nature 371:164–168

    CAS  PubMed  Google Scholar 

  101. Gromoll J, Schulz A, Borta H et al (2002) Homozygous mutation within the conserved Ala-Phe-Asn-Glu-Thr motif of exon 7 of the LH receptor causes male pseudohermaphroditism. Eur J Endocrinol 147:597–608

    CAS  PubMed  Google Scholar 

  102. Lalioti MD (2011) Impact of follicle stimulating hormone receptor variants in fertility. Curr Opin Obstet Gynecol 23:158–167

    PubMed  Google Scholar 

  103. Casas-González P, Scaglia HE, Pérez-Solís MA et al (2012) Normal testicular function without detectable follicle-stimulating hormone. A novel mutation in the follicle-stimulating hormone receptor gene leading to apparent constitutive activity and impaired agonist-induced desensitization and internalization. Mol Cell Endocrinol 364:71–82

    PubMed  Google Scholar 

  104. Latronico AC, Anasti J, Arnhold IJ et al (1995) A novel mutation of the luteinizing hormone receptor gene causing male gonadotropin-independent precocious puberty. J Clin Endocrinol Metab 80:2490–2494

    CAS  PubMed  Google Scholar 

  105. Kosugi S, Van Dop C, Geffner ME et al (1995) Characterization of heterogeneous mutations causing constitutive activation of the luteinizing hormone receptor in familial male precocious puberty. Hum Mol Genet 4:183–188

    CAS  PubMed  Google Scholar 

  106. Seminara SB, Messager S, Chatzidaki EE et al (2003) The GPR54 gene as a regulator of puberty. N Engl J Med 349:1614–1627

    CAS  PubMed  Google Scholar 

  107. de Roux N, Genin E, Carel JC et al (2003) Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54. Proc Natl Acad Sci U S A 100:10972–10976

    PubMed Central  PubMed  Google Scholar 

  108. Franco B, Guioli S, Pragliola A et al (1991) A gene deleted in Kallmanns syndrome shares homology with neural cell-adhesion and axonal path-finding molecules. Nature 353:529–536

    CAS  PubMed  Google Scholar 

  109. Legouis R, Hardelin JP, Levilliers J et al (1991) The candidate gene for the X-linked Kallmann syndrome encodes a protein related to adhesion molecules. Cell 67:423–435

    CAS  PubMed  Google Scholar 

  110. Habiby RL, Boepple P, Nachtigall L et al (1996) Adrenal hypoplasia congenita with hypogonadotropic hypogonadism—evidence that DAX-1 mutations lead to combined hypothalamic and pituitary defects in gonadotropin production. J Clin Invest 98:1055–1062

    CAS  PubMed Central  PubMed  Google Scholar 

  111. Beranova M, Oliveira LMB, Bedecarrats GY et al (2001) Prevalence, phenotypic spectrum, and modes of inheritance of gonadotropin-releasing hormone receptor mutations in idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab 86:1580–1588

    CAS  PubMed  Google Scholar 

  112. Monnier C, Dodé C, Fabre L et al (2009) PROKR2 missense mutations associated with Kallmann syndrome impair receptor signalling activity. Hum Mol Genet 18:75–81

    CAS  PubMed Central  PubMed  Google Scholar 

  113. Topaloglu AK, Reimann F, Guclu M et al (2009) TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for Neurokinin B in the central control of reproduction. Nat Genet 41:354–358

    CAS  PubMed  Google Scholar 

  114. deRoux N, Young J, Misrahi M et al (1997) A family with hypogonadotropic hypogonadism and mutations in the gonadotropin-releasing hormone receptor. N Engl J Med 337:1597–1602

    CAS  Google Scholar 

  115. Layman LC, Cohen DP, Jin M et al (1998) Mutations in gonadotropin-releasing hormone receptor gene cause hypogonadotropic hypogonadism. Nat Genet 18:14–15

    CAS  PubMed  Google Scholar 

  116. Lin L, Conway GS, Hill NR et al (2006) A homozygous R262Q mutation in the gonadotropin-releasing hormone receptor presenting as constitutional delay of growth and puberty with subsequent borderline oligospermia. J Clin Endocrinol Metab 91:5117–5121

    CAS  PubMed Central  PubMed  Google Scholar 

  117. Hoffmann SH, ter Laak T, Kuhne R et al (2000) Residues within transmembrane helices 2 and 5 of the human gonadotropin-releasing hormone receptor contribute to agonist and antagonist binding. Mol Endocrinol 14:1099–1115

    CAS  PubMed  Google Scholar 

  118. Noel SD, Kaiser UB (2011) G protein-coupled receptors involved in GnRH regulation: molecular insights from human disease. Mol Cell Endocrinol 346:91–101

    CAS  PubMed Central  PubMed  Google Scholar 

  119. Tsigos C, Arai K, Hung W et al (1993) Hereditary isolated glucocorticoid deficiency is associated with abnormalities of the adrenocorticotropin receptor gene. J Clin Invest 92:2458–2461

    CAS  PubMed Central  PubMed  Google Scholar 

  120. Tsigos C, Tsiotra P, Garibaldi LR et al (2000) Mutations of the ACTH receptor gene in a new family with isolated glucocorticoid deficiency. Mol Genet Metab 71:646–650

    CAS  PubMed  Google Scholar 

  121. Hughes CR, Chung TT, Habeb AM et al (2010) Missense mutations in the melanocortin 2 receptor accessory protein that lead to late onset familial glucocorticoid deficiency type 2. J Clin Endocrinol Metab 95:3497–3501

    CAS  PubMed  Google Scholar 

  122. Metherell LA, Naville D, Halaby G et al (2000) Nonclassic lipoid congenital adrenal hyperplasia masquerading as familial glucocorticoid deficiency. J Clin Endocrinol Metab 94:3865–3871

    Google Scholar 

  123. Spanakis E, Milord E, Gragnoli C (2008) AVPR2 variants and mutations in nephrogenic diabetes insipidus: review and missense mutation significance. J Cell Physiol 217:605–617

    CAS  PubMed  Google Scholar 

  124. Bichet DG, El Tarazi A, Matar J et al (2012) Aquaporin-2: new mutations responsible for autosomal recessive nephrogenic diabetes insipidus—update and epidemiology. Clin Kidney J 5:195–202

    CAS  Google Scholar 

  125. Rosenthal W, Seibold A, Antaramian A et al (1992) Molecular identification of the gene responsible for congenital nephrogenic diabetes insipidus. Nature 359:233–235

    CAS  PubMed  Google Scholar 

  126. Feinstein TN, Yui N, Webber MJ et al (2013) Noncanonical control of vasopressin receptor type 2 signaling by retromer and arrestin. J Biol Chem 288:27849–27860

    CAS  PubMed  Google Scholar 

  127. Los EL, Deen PM, Robben JH (2010) Potential of nonpeptide (ant)agonists to rescue vasopressin V2 receptor mutants for the treatment of X-linked nephrogenic diabetes insipidus. J Neuroendocrinol 22:393–399

    CAS  PubMed  Google Scholar 

  128. McKusick VA (2007) Mendelian Inheritance in Man and its online version, OMIM. Am J Hum Genet 80:588–604

    CAS  PubMed Central  PubMed  Google Scholar 

  129. Fujiwara TM, Bichet DG (2005) Molecular biology of hereditary diabetes insipidus. J Am Soc Nephrol 16:2836–2846

    CAS  PubMed  Google Scholar 

  130. Arthus M-F, Lonergan M, Crumley MJ et al (2000) Report of 33 novel AVPR2 mutations and analysis of 117 families with X-linked nephrogenic diabetes insipidus. J Am Soc Nephrol 11:1044–1054

    CAS  PubMed  Google Scholar 

  131. Nomura Y, Onigata K, Nagashima T et al (1997) Detection of skewed X-inactivation in two female carriers of vasopressin type 2 receptor gene mutation. J Clin Endocrinol Metab 82:3434–3437

    CAS  PubMed  Google Scholar 

  132. Bichet DG, Arthus M-F, Lonergan M et al (1993) X-linked nephrogenic diabetes insipidus mutations in North America and the Hopewell hypothesis. J Clin Invest 92:1262–1268

    CAS  PubMed Central  PubMed  Google Scholar 

  133. Hobbs HH, Russell DW, Brown MS et al (1990) The LDL receptor locus in familial hypercholesterolemia: mutational analysis of a membrane protein. Annu Rev Genet 24:133–170

    CAS  PubMed  Google Scholar 

  134. Wuller S, Wiesner B, Loffler A et al (2004) Pharmacochaperones post-translationally enhance cell surface expression by increasing conformational stability of wild-type and mutant vasopressin V2 receptors. J Biol Chem 279:47254–47263

    PubMed  Google Scholar 

  135. Hermosilla R, Oueslati M, Donalies U et al (2004) Disease-causing V(2) vasopressin receptors are retained in different compartments of the early secretory pathway. Traffic 5:993–1005

    CAS  PubMed  Google Scholar 

  136. Bernier V, Morello JP, Zarruk A et al (2006) Pharmacologic chaperones as a potential treatment for X-linked nephrogenic diabetes insipidus. J Am Soc Nephrol 17:232–243

    CAS  PubMed  Google Scholar 

  137. Morello JP, Salahpour A, Laperrière A et al (2000) Pharmacological chaperones rescue cell-surface expression and function of misfolded V2 vasopressin receptor mutants. J Clin Invest 105:887–895

    CAS  PubMed Central  PubMed  Google Scholar 

  138. Schoneberg T, Schulz A, Biebermann H et al (2004) Mutant G-protein-coupled receptors as a cause of human diseases. Pharmacol Ther 104:173–206

    PubMed  Google Scholar 

  139. Romisch K (2004) A cure for traffic jams: small molecule chaperones in the endoplasmic reticulum. Traffic 5:815–820

    PubMed  Google Scholar 

  140. Tamarappoo BK, Verkman AS (1998) Defective aquaporin-2 trafficking in nephrogenic diabetes insipidus and correction by chemical chaperones. J Clin Invest 101:2257–2267

    CAS  PubMed Central  PubMed  Google Scholar 

  141. Kunchaparty S, Palcso M, Berkman J et al (1999) Defective processing and expression of thiazide-sensitive Na-Cl cotransporter as a cause of Gitelman’s syndrome. Am J Physiol 277:F643–F649

    CAS  PubMed  Google Scholar 

  142. Hayama A, Rai T, Sasaki S, Uchida S (2003) Molecular mechanisms of Bartter syndrome caused by mutations in the BSND gene. Histochem Cell Biol 119:485–493

    CAS  PubMed  Google Scholar 

  143. Peters M, Ermert S, Jeck N et al (2003) Classification and rescue of ROMK mutations underlying hyperprostaglandin E syndrome/antenatal Bartter syndrome. Kidney Int 64:923–932

    CAS  PubMed  Google Scholar 

  144. Chillaron J, Estevez R, Samarzija I et al (1997) An intracellular trafficking defect in type I cystinuria rBAT mutants M467T and M467K. J Biol Chem 272:9543–9549

    CAS  PubMed  Google Scholar 

  145. Bonnardeaux A, Bichet DG (2012) In: Taal MW, Chertow GM, Marsden PA, Skorecki K, Yu ASL, Brenner BM (Eds.)Inherited disorders of the renal tubule in Brenner & Rector’s the kidney, vol 2. 9th ed. Elsevier Saunders, Philadelphia, PA. pp. 1584–1625

    Google Scholar 

  146. Lomas DA, Evans DL, Finch JT et al (1992) The mechanism of Z alpha 1-antitrypsin accumulation in the liver. Nature 357:605–607

    CAS  PubMed  Google Scholar 

  147. Lawless MW, Greene CM, Mulgrew A et al (2004) Activation of endoplasmic reticulum-specific stress responses associated with the conformational disease Z alpha 1-antitrypsin deficiency. J Immunol 172:5722–5726

    CAS  PubMed  Google Scholar 

  148. Cohen FE, Kelly JW (2003) Therapeutic approaches to protein-misfolding diseases. Nature 426:905–909

    CAS  PubMed  Google Scholar 

  149. Ulloa-Aguirre A, Janovick JA, Brothers SP et al (2004) Pharmacologic rescue of conformationally-defective proteins: implications for the treatment of human disease. Traffic 5:821–837

    CAS  PubMed  Google Scholar 

  150. Bernier V, Lagace M, Lonergan M et al (2004) Functional rescue of the constitutively internalized V2 vasopressin receptor mutant R137H by the pharmacological chaperone action of SR49059. Mol Endocrinol 18:2074–2084

    CAS  PubMed  Google Scholar 

  151. Barak LS, Oakley RH, Laporte SA et al (2001) Constitutive arrestin-mediated desensitization of a human vasopressin receptor mutant associated with nephrogenic diabetes insipidus. Proc Natl Acad Sci U S A 98:93–98

    CAS  PubMed Central  PubMed  Google Scholar 

  152. Soule S, Florkowski C, Potter H et al (2008) Intermittent severe, symptomatic hyponatraemia due to the nephrogenic syndrome of inappropriate antidiuresis. Ann Clin Biochem 45:520–523

    CAS  PubMed  Google Scholar 

  153. Feldman BJ, Rosenthal SM, Vargas GA et al (2005) Nephrogenic syndrome of inappropriate antidiuresis. N Engl J Med 352:1884–1890

    CAS  PubMed  Google Scholar 

  154. Marcialis MA, Faa V, Fanos V et al (2008) Neonatal onset of nephrogenic syndrome of inappropriate antidiuresis. Pediatr Nephrol 23:2267–2271

    PubMed  Google Scholar 

  155. Decaux G, Vandergheynst F, Bouko Y et al (2007) Nephrogenic syndrome of inappropriate antidiuresis in adults: high phenotypic variability in men and women from a large pedigree. J Am Soc Nephrol 18:606–612

    CAS  PubMed  Google Scholar 

  156. Carpentier E, Greenbaum LA, Rochdi D et al (2012) Identification and characterization of an activating F229V substitution in the V2 vasopressin receptor in an infant with NSIAD. J Am Soc Nephrol 23:1635–1640

    CAS  PubMed Central  PubMed  Google Scholar 

  157. Kalenga K, Persu A, Goffin E et al (2002) Intrafamilial phenotype variability in nephrogenic diabetes insipidus. Am J Kidney Dis 39:737–743

    PubMed  Google Scholar 

  158. Kocan M, See HB, Sampaio NG et al (2009) Agonist-independent interactions between beta-arrestins and mutant vasopressin type II receptors associated with nephrogenic syndrome of inappropriate antidiuresis. Mol Endocrinol 23:559–571

    CAS  PubMed Central  PubMed  Google Scholar 

  159. Brooks A, Oostra BA, Hofstra RM (2005) Studying the genetics of Hirschsprung’s disease: unraveling an oligogenic disorder. Clin Genet 67:6–14

    CAS  PubMed  Google Scholar 

  160. Martucciello G, Ceccherini I, Lerone M et al (2000) Pathogenesis of Hirschsprung’s disease. J Pediatr Surg 35:1017–1025

    CAS  PubMed  Google Scholar 

  161. Sánchez-Mejías A, Fernández RM, López-Alonso M et al (2010) New roles of EDNRB and EDN3 in the pathogenesis of Hirschsprung disease. Genet Med 12:39–43

    PubMed  Google Scholar 

  162. Puffenberger EG, Hosoda K, Washington SS et al (1994) A missense mutation of the endothelin-B receptor gene in multigenic Hirschsprung’s disease. Cell 79:1257–1266

    CAS  PubMed  Google Scholar 

  163. Attie T, Till M, Pelet A et al (1995) Mutation of the endothelin-receptor-B gene in Waardenburg-Hirschsprung-disease. Hum Mol Genet 4:2407–2409

    CAS  PubMed  Google Scholar 

  164. Hofstra RMW, Osinga J, TanSindhunata G et al (1996) A homozygous mutation in the endothelin-3 gene associated with a combined Waardenburg type 2 and Hirschsprung phenotype (Shah-Waardenburg syndrome). Nat Genet 12:445–447

    CAS  PubMed  Google Scholar 

  165. Hofstra RMW, Valdenaire O, Arch E et al (1999) A loss-of-function mutation in the endothelin-converting enzyme 1 (ECE-1) associated with Hirschsprung disease, cardiac defects, and autonomic dysfunction. Am J Hum Genet 64:304–308

    CAS  PubMed Central  PubMed  Google Scholar 

  166. Fuchs S, Amiel J, Claudel S et al (2001) Functional characterization of three mutations of the endothelin B receptor gene in patients with Hirschsprung’s disease: evidence for selective loss of G(i) coupling. Mol Med 7:115–124

    CAS  PubMed Central  PubMed  Google Scholar 

  167. Imamura F, Arimoto I, Fujiyoshi Y, Doi T (2000) W276 mutation in the endothelin receptor subtype B impairs G(q) but not G(i) or G(o) coupling. Biochemistry 39:686–692

    CAS  PubMed  Google Scholar 

  168. Hollopeter G, Jantzen HM, Vincent D et al (2001) Identification of the platelet ADP receptor targeted by antithrombotic drugs. Nature 409:202–207

    CAS  PubMed  Google Scholar 

  169. Jefferson BK, Foster JH, McCarthy JJ et al (2005) Aspirin resistance and a single gene. Am J Cardiol 95:805–808

    CAS  PubMed  Google Scholar 

  170. Armstrong PCJ, Leadbeater PD, Chan MV et al (2011) In the presence of strong P2Y12 receptor blockade, aspirin provides little additional inhibition of platelet aggregation. J Thromb Haemost 9:552–561

    CAS  PubMed Central  PubMed  Google Scholar 

  171. Laitinen T, Polvi A, Rydman P et al (2004) Characterization of a common susceptibility locus for asthma-related traits. Science 304:300–304

    CAS  PubMed  Google Scholar 

  172. Kormann MSD, Carr D, Klopp N et al (2005) G-protein-coupled receptor polymorphisms are associated with asthma in a large German population. Am J Respir Crit Care Med 171:1358–1362

    PubMed  Google Scholar 

  173. Melen E, Bruce S, Doekes G et al (2005) Haplotypes of G protein-coupled receptor 154 are associated with childhood allergy and asthma. Am J Respir Crit Care Med 171:1089–1095

    PubMed  Google Scholar 

  174. Pietras CO, Vendelin J, Anedda F, Bruce S, Adner M, Sundman L, Pulkkinen V, Alenius H, D’Amato M, Söderhäll C, Kere J (2011) The asthma candidate gene NPSR1 mediates isoform specific downstream signalling. BMC Pulm Med 11:39. doi:10.1186/1471-2466-11-39

    PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from the Scottish Rite Foundation of Canada and the Ontario Brain Institute (OBI)—Eplink Project; The National Science and Engineering Research Council (NSERC) and the Dairy Farmers of Canada (DFC). The Canadian Institutes of Health Research/Epilepsy Canada provided postdoctoral fellowship support to Dr. Thompson.

Author information

Authors and Affiliations

  1. Department of Pharmacology, University of Toronto, 1 King’s College Circle, Toronto, ON, Canada, M5S 1A8

    Miles D. Thompson

  2. Departments of Medicine, Physiology and Human Genetics, McGill University, Montreal, QC, Canada

    Geoffrey N. Hendy

  3. Calcium Research Laboratory and, Hormones and Cancer Research Unit, Royal Victoria Hospital and McGill University Health Centre, Montreal, QC, Canada

    Geoffrey N. Hendy

  4. Neurogenetics, Surrey Place Centre, Toronto, ON, Canada

    Maire E. Percy

  5. Departments of Physiology and Obstetrics & Gynaecology, University of Toronto, Toronto, ON, Canada

    Maire E. Percy

  6. Department of Physiology and Medicine, Hôpital du Sacré-Coeur, Université de Montréal, Montréal, QC, Canada

    Daniel G. Bichet

  7. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada

    David E. C. Cole

Authors
  1. Miles D. Thompson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Geoffrey N. Hendy
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Maire E. Percy
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Daniel G. Bichet
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. David E. C. Cole
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Miles D. Thompson .

Editor information

Editors and Affiliations

  1. PharmTao, Santa Clara, California, USA

    Qing Yan

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer Science+Business Media New York

About this protocol

Cite this protocol

Thompson, M.D., Hendy, G.N., Percy, M.E., Bichet, D.G., Cole, D.E.C. (2014). G Protein-Coupled Receptor Mutations and Human Genetic Disease. In: Yan, Q. (eds) Pharmacogenomics in Drug Discovery and Development. Methods in Molecular Biology, vol 1175. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-0956-8_8

Download citation

  • DOI: https://doi.org/10.1007/978-1-4939-0956-8_8

  • Published:

  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4939-0955-1

  • Online ISBN: 978-1-4939-0956-8

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation