PMID- 25150870
OWN - NLM
STAT- MEDLINE
DCOM- 20150511
LR  - 20140825
IS  - 1940-6029 (Electronic)
IS  - 1064-3745 (Linking)
VI  - 1175
DP  - 2014
TI  - G protein-coupled receptor mutations and human genetic disease.
PG  - 153-87
LID - 10.1007/978-1-4939-0956-8_8 [doi]
AB  - 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-beta, 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.
FAU - Thompson, Miles D
AU  - Thompson MD
AD  - Department of Pharmacology, University of Toronto, 1 King's College Circle, 
      Toronto, ON, Canada, M5S 1A8, miles.thompson@utoronto.ca.
FAU - Hendy, Geoffrey N
AU  - Hendy GN
FAU - Percy, Maire E
AU  - Percy ME
FAU - Bichet, Daniel G
AU  - Bichet DG
FAU - Cole, David E C
AU  - Cole DE
LA  - eng
GR  - Canadian Institutes of Health Research/Canada
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Review
PL  - United States
TA  - Methods Mol Biol
JT  - Methods in molecular biology (Clifton, N.J.)
JID - 9214969
RN  - 0 (Receptors, G-Protein-Coupled)
SB  - IM
MH  - Animals
MH  - *Genetic Association Studies
MH  - Genetic Diseases, Inborn/diagnosis/genetics/metabolism
MH  - Humans
MH  - *Mutation
MH  - Receptors, G-Protein-Coupled/*genetics/metabolism
EDAT- 2014/08/26 06:00
MHDA- 2015/05/12 06:00
CRDT- 2014/08/25 06:00
PHST- 2014/08/25 06:00 [entrez]
PHST- 2014/08/26 06:00 [pubmed]
PHST- 2015/05/12 06:00 [medline]
AID - 10.1007/978-1-4939-0956-8_8 [doi]
PST - ppublish
SO  - Methods Mol Biol. 2014;1175:153-87. doi: 10.1007/978-1-4939-0956-8_8.